Autophagy inhibitors

ABSTRACT

The present invention relates to compounds of formulas III and V that are useful as pharmaceutical agents, particularly as autophagy inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 14/946,337 filed on Nov. 19, 2015, which is a divisional ofU.S. patent application Ser. No. 14/116,650 filed Nov. 8, 2014, which isa 35 U.S.C. § 371 United States National Phase filing of, and claimspriority to, PCT International Application No. PCT/US2012/037158 filedMay 9, 2012, which claims the benefit under 35 U.S.C. § 119 of U.S.Provisional Application Ser. No. 61/483,991 filed on May 9, 2011, thecontents of each of which is hereby incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to compounds that are useful aspharmaceutical agents, particularly as autophagy inhibitors.

BACKGROUND OF THE INVENTION

Macroautophagy (autophagy) is an important mechanism for targetingcellular components including proteins, protein aggregates, andorganelles for degradation in lysosomes. This catabolic, cellularself-digestion process is induced in response to starvation or stress,causing the formation of double membrane vesicles called autophagosomesthat engulf proteins and organelles. Autophagosomes then fuse withlysosomes where the autophagosome and their cargo are degraded. Thislysosome-mediated cellular self-digestion serves to recycleintracellular nutrients to sustain cell metabolism during starvation andto eliminate damaged proteins and organelles that accumulate duringstress. Although elimination of individual proteins occurs by theubiquitin-mediated proteasome degradation pathway, the autophagy pathwaycan eliminate protein aggregates and organelles. Thus, autophagycomplements and overlaps with proteasome function to prevent theaccumulation of damaged cellular components during starvation andstress. Through these functions, autophagy is an essential cellularstress response that maintains protein and organelle quality control,protects the genome from damage, and sustains cell and mammalianviability.

Autophagy is controlled by ATG proteins, initially identified in yeast,for which there are mammalian homologues (Levine, B., and Kroemer, G.(2008), Autophagy in the pathogenesis of disease, Cell 132, 27-42). ATGproteins are comprised of kinases, proteases, and two ubiquitin-likeconjugation systems that likely function in concert with a host ofunknown cellular proteins to control autophagosome formation, cargorecognition, engulfment, and trafficking to lysosomes.

Autophagy dysfunction is a major contributor to diseases including, butnot limited to, neurodegeneration, liver disease, and cancer. Many humanneurodegenerative diseases are associated with aberrant mutant and/orpolyubiquitinated protein accumulation and excessive neuronal celldeath.

Autophagy is also induced by stress and starvation in tumor cells, whereit predominantly provides a prosurvival function. Metabolic stress iscommon, and autophagy localizes to metabolically-stressed tumor regions.Autophagy has been identified as an important survival pathway inepithelial tumor cells that enables long-term survival to metabolicstress (Degenhardt, K., et al. (2006), Autophagy promotes tumor cellsurvival and restricts necrosis, inflammation, and tumorigenesis, CancerCell 10, 51-64; Jin, S., and White, E. (2007), Role of autophagy incancer: management of metabolic stress. Autophagy 3, 28-31;Karantza-Wadsworth, V., et al., (2007), Autophagy mitigates metabolicstress and genome damage in mammary tumorigenesis, Genes Dev 21,1621-1635; Mathew, R. et al., (2007a), Role of autophagy in cancer, NatRev Cancer 7, 961-967; Mathew, R., et al. (2007b), Autophagy suppressestumor progression by limiting chromosomal instability, Genes Dev 21,1367-1381). Tumor cells with defined defects in autophagy accumulatep62-containing protein aggregates, damage DNA, and die in response tostress, whereas those with intact autophagy can survive for weeks,utilizing the autophagy survival pathway. Thus, autophagy prevents tumorcell damage and maintains metabolism. Tumor cells exploit this survivalfunction to remain dormant, only to reemerge under more favorableconditions.

Paradoxically, autophagy defects through allelic loss of the essentialautophagy gene becliril or through constitutive activation of theautophagy-suppressing PI-3 kinase/mTOR pathway are common in humantumors. Roughly half of human cancers may have impaired autophagy,either due to constitutive activation of the PI-3 kinase pathway orallelic loss of the essential autophagy gene beclinl, rendering themparticularly susceptible to metabolic stress and autophagy inhibition(Jin et al., 2007; Jin, S., and White, E. (2008).

The importance of autophagy in cellular garbage disposal is clear, sinceautophagy is the only identified mechanism for the turnover of largecellular structures, such as organdies and protein aggregates. Howorgandies are recognized and directed to autophagosomes for degradationmay involve organelle-specific processes, such as mitophagy andER-phagy, that may mitigate oxidative stress emanating fromdysfunctional organelles. Damaged proteins that accumulate during stresscan be refolded, ubiquitinated, and degraded by the proteasome pathway,or aggregated and degraded by autophagy. To direct damaged or unfoldedproteins to the autophagy pathway, p62 binds to polyubiquitinatedproteins, forming protein aggregates by oligomerization, and to Atg8/LC3on the autophagosome membrane to target aggregates to autophagosomes fordegradation. Protein aggregation may be a protective mechanism to limitcellular exposure to toxic proteins through sequestration, as well as anefficient packaging and delivery mechanism that collects and directsdamaged proteins to autophagosomes. Thus, the inability to dispose ofp62 aggregates through autophagy appears to be toxic to normal tissues.

The ATG6/Beclin1-Vps34-ATG8/LC3 complex regulates autophagosomeformation. LC3 cleavage, lipidation, and membrane translocation arefrequently utilized to monitor autophagy induction. The mechanism bywhich starvation and stress activate autophagy is controlled in partthrough the PI-3 kinase pathway via the protein kinase mTOR. Growthfactor and nutrient availability promote mTOR activation that suppressesautophagy, whereas starvation and mTOR inactivation stimulate autophagy(Klionsky (2007), Nat Rev Mol Cell Biol 8, 931-937). While there areother mechanisms to regulate autophagy, mTOR provides a link betweennutrient and growth factor availability, growth control, autophagy, andmetabolism.

Autophagy plays an essential role in maintaining protein qualitycontrol, while defective autophagy is involved in the development ofdiseases including, but not limited to, cancer, neurodegenerativedisorders, autoimmune disorders, cardiovascular disorders, metabolicdisorders, hamartoma syndrome, genetic muscle disorders, and myopathies.Therefore, there exists a need for identification of inhibitors of theautophagy survival pathway in, for example, cancer cells. Suchinhibitors of autophagy can be used in the prevention, palliation,and/or treatment of cancer.

SUMMARY OF THE INVENTION

Disclosed is a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein:

Q is CH or N;

R_(N) is —H, C₁-C₃ alkyl, or —CO—R_(N-1), where R_(N-1) is C₁-C₃ alkylor phenyl;

R₁ is —H, —F, —Cl, —Br, or —CF₃;

R₂ is —CH(R₂₋₁)_(n1)—(CH₂)_(n2)—W_(n3)—X or —C*H—CH₂—CH₂—X₂—X₃—;

-   -   n₁ is 0 or 1;    -   R₂₋₁ is —H, C₁-C₃ alkyl, or C₃ cycloalkyl;    -   n₂ is 0 through 3;    -   n₃ is 0 or 1, with the provisos that (1) when n₁ or n₂ are other        than 0, n₃ must be 0, (2) when n₃ is 1, n₁ and n₂ are both        0; (3) when n₁ is 1, X₁₋₂ and X₁₋₃ must be taken together e        attached nitrogen atom to form a monocyclic structure;    -   W is a cyclic structure of three through seven atoms consisting        of carbon, nitrogen, and sulfur, with the proviso that there not        be more than one nitrogen or sulfur atom in the ring optionally        containing 1 through 3 double bonds;    -   X is —NX₁₋₂X₁₋₃, where X₁₋₂ and X₁₋₃ are the same or different        and are C₁-C₄ substituted with one —OCH₃, —O—C₂H₅, alkoxy,        haloalkoxy, haloalkyl, cyclopropyl, —CH₂-cyclopropyl,        cyclobutyl, —SO₂—X₁₋₄ where X₁₋₄ is selected from —H and C₁-C₃        alkyl, —CO—X₁₋₄ where X₁₋₄ is as defined above, and where the        X₁₋₂ and X₁₋₃ are taken together with the attached nitrogen atom        to form a monocyclic structure consisting of four through seven        atoms selected from the group consisting of carbon and nitrogen,        with the proviso that the ring does not have more than two        nitrogen atoms, —O—X₁₋₂ where X₁₋₂ is defined above;    -   X₂ is or —NX₁₋₂ or —O—, where X₁₋₂ is defined above;    -   X₃ is —C*H—(CH₂)_(n4)— or —(CH₂)_(n4)—C*H— where n₄ is 0 through        2 and by convention * means the atoms marked with an asterisk        (*) are bonded to each other resulting in the formation of a        ring;

-   R₃ is —H, —F, —Cl, —Br, —CF₃, —OR₃₋₁ where R₃₋₁ is —H, C₁-C₆ alkyl    or —CO—R₃₋₂ where R₃₋₂ is C₁-C₃ alkyl or phenyl, —N(R₃₋₁)₂ where the    R₃₋₁ are the same or different and are as defined above, —SR₃₋₁    where R₃₋₁ is as defined above, —S(O)—R₃₋₁ where R₃₋₁ is as defined    above, or —SO₂—R₃₋₁ where R₃₋₁ is as defined above;

-   R₄ is —H, —F, —Cl, —Br, —CF₃, —OR₄₋₁ where R₄₋₁ is —H, C₁-C₆ alkyl    or —CO—R₄₋₂ where R₄₋₂ is C₁-C₃ alkyl or phenyl, —N(R₄₋₁)₂ where the    R₄₋₁ are the same or different and are as defined above, —SR₄₋₁    where R₄₋₁ is as defined above, —S(O)—R₄₋₁ where R₄₋₁ is as defined    above, or —SO₂—R₄₋₁ where R₄₋₁ is as defined above;

-   R₅ is —H, —F, —Cl, —Br, —CF₃, —OR₅₋₁ where R₅₋₁ is —H, C₁-C₆ alkyl    or —CO—R₅₋₂ where R₅₋₂ is C₁-C₃ alkyl or phenyl, —N(R₅₋₁)₂ where the    R₅₋₁ are the same or different and are as defined above, —SR₅₋₁    where R₅₋₁ is as defined above, —S(O)—R₅₋₁ where R₅₋₁ is as defined    above, or —SO₂—R₅₋₁ where R₅₋₁ is as defined above;    -   with the proviso that one of R₁, R₃, R₄ and R₅ must be other        than —H.

Also disclosed is a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein:

n is 0 or 1;

R₂ is —CH(R₂₋₁)_(n1)—(CH₂)_(n2)—W_(n3)—X

-   -   n₁ is 0 or 1;    -   R₂₋₁ is —H or C₁-C₃ alkyl;    -   n₂ is 0 through 3;    -   n₃ is 0 or 1, with the provisos (1) that when n₁ or n₂ are other        than 0, n₃ must be 0 and (2) that when n₃ is 1, n₁ and n₂ are        both 0;    -   W is a cyclic structure of three through seven atoms consisting        of carbon, nitrogen, and sulfur with the proviso that there not        be more than one nitrogen or sulfur atom in the ring optionally        containing 1 through 3 double bonds;    -   X is —NX₁₋₂X₁₋₃ or —C*H—CH₂—CH₂—X₂—X₃—;    -   X₁₋₂ and X₁₋₃ are the same or different and are —H, C₁-C₄        optionally substituted with one —OH, —OCH₃, —O—C₂H₅,        cyclopropyl, —CH₂-cyclopropyl, cyclobutyl,        —CH₂—CH₂—N(X₁₋₄)(X₁₋₅) where X₁₋₄ and X₁₋₅ are the same or        different and are —H and C₁-C₃ alkyl, —SO₂—X₁₋₄ where X₁₋₄ is as        defined above, —CO—X₁₋₄ where X₁₋₄ is as defined above, and        where the X₁₋₂ and X₁₋₃ are taken together with the attached        nitrogen atom to form a monocyclic structure consisting of four        through seven atoms selected from the group consisting of        carbon, nitrogen and oxygen with the provisos that the ring not        have more than one oxygen atom and not more than two nitrogen        atoms; —O—X₁₋₂ where X₁₋₂ is as defined above;    -   X₂ is —NX₁₋₂— or —O—,    -   X₃ is —C*H—(CH₂)_(m4)— or —(CH₂)_(m4)—C*H— where in₄ is 0        through 2 and by convention * means the atoms marked with an        asterisk (*) are bonded to each other resulting in the formation        of a ring; and where R₁ and R_(N) are defined above.

Also disclosed are pharmaceutical compositions containing compounds offormulas III or V.

Also disclosed are processes for preparing compounds of formulas III orV.

Also disclosed are methods of treating cancer, neurodegenerativedisorders, autoimmune disorders, cardiovascular disorders, metabolicdisorders, hamartoma syndrome, genetic muscle disorders, and myopathies,comprising administration to a patient in need of such treatment acompound of formula III or V or a pharmaceutically salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A depicts tumor cell inhibition by Example 10 in cell lines H292,HCT116, and A375.

FIG. 1B depicts tumor cell inhibition by Example 10 in cell linesHCC1569, A498, and N87.

FIG. 2 depicts tumor cell inhibition by Example 10 in PLX-4032 resistantmelanoma cell lines UACC1093 and UACC647.

FIG. 3A depicts tumor cell inhibition by Example 7 in cell line A375.

FIG. 3B depicts tumor cell inhibition by Example 26 in cell line A375.

FIG. 3C depicts tumor cell inhibition by Example 27 in cell line A375.

FIG. 4A depicts tumor cell inhibition by Example 10 in combination withPLX-4032 in cell line UACC1093.

FIG. 4B depicts tumor cell inhibition by Example 10 in combination withTemozolomide in cell line UACC1093.

FIG. 4C depicts tumor cell inhibition by Example 10 in combination withPLX-4032 in cell line UACC647.

FIG. 4D depicts tumor cell inhibition by Example 10 in combination withTemozolomide in cell line UACC647.

FIG. 5 depicts tumor cell weight in mice treated with Example 10.

FIG. 6A depicts a graph showing mean intensity quantification of redpunctae on a dose response of Example 7 and Example 26 using imageclysis software.

FIG. 6B depicts a graph showing percentage of cell viability after 48hours of treatment with Example 7 and Example 26.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations and Definitions

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

Abbreviation Meaning Ac Acetyl bALP Bone-specific alkaline phosphataseBr Broad ° C. Degrees Celsius c- Cyclo CBZ CarboBenZoxy =benzyloxycarbonyl CTx Cross-linked C-terminal telopeptides of type-1collagen d Doublet dd Doublet of doublet dt Doublet of triplet DCMDichloromethane DME 1,2-dimethoxyethane DMF N,N-Dimethylformamide DMSOdimethyl sulfoxide g Gram(s) h or hr Hour(s) HPLC High pressure liquidchromatography L Liter(s) M Molar or molarity m Multiplet mgMilligram(s) MHz Megahertz (frequency) Min Minute(s) mL Milliliter(s) μLMicroliter(s) μM Micromole(s) or micromolar mM Millimolar MmolMillimole(s) Mol Mole(s) MS Mass spectral analysis N Normal or normalitynM Nanomolar NMR Nuclear magnetic resonance spectroscopy q Quartet RTRoom temperature s Singlet t or tr Triplet TFA Trifluoroacetic acid THFTetrahydrofuran

The symbol “—” means a single bond, “═” means a double bond, “≡” means atriple bond. The symbol “

” refers to a group on a double-bond as occupying either position on theterminus of a double bond to which the symbol is attached; that is, thegeometry, E- or Z-, of the double bond is ambiguous. When a group isdepicted removed from its parent formula, the “

” symbol will be used at the end of the bond which was theoreticallycleaved in order to separate the group from its parent structuralformula.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

In this application, some ring structures are depicted generically andwill be described textually. For example, in the schematic below, if inthe structure on the left, ring A is used to describe a “spirocyclyl,”then if ring A is cyclopropyl, there are at most four hydrogens on ringA (when “R” can also be —H). In another example, as depicted on theright side of the schematic below, if ring B is used to describe a“phenylene” then there can be at most four hydrogens on ring B (assumingdepicted cleaved bonds are not C—H bonds).

If a group “R” is depicted as “floating” on a ring system, as forexample in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the formulae:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused ring system, assuming replacement of a depicted (forexample the —NH— in the formula above), implied (for example as in theformula above, where the hydrogens are not shown but understood to bepresent), or expressly defined hydrogen (for example where in theformula above, “X” equals ═CH—) from one of the ring atoms, so long as astable structure is formed. In the example depicted, the “R” group mayreside on either the 5-membered or the 6-membered ring of the fused ringsystem. In the formula depicted above, when y is 2 for example, then thetwo “R's” may reside on any two atoms of the ring system, again assumingeach replaces a depicted, implied, or expressly defined hydrogen on thering.

When there are more than one such depicted “floating” groups, as forexample in the formulae:

where there are two groups, namely, the “R” and the bond indicatingattachment to a parent structure; then, unless otherwise defined, the“floating” groups may reside on any atoms of the ring system, againassuming each replaces a depicted, implied, or expressly definedhydrogen on the ring.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. A simple example iswhen R is a methyl group; there can exist a geminal dimethyl on a carbonof the depicted ring (an “annular” carbon). In another example, two R'son the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring (a “spirocyclyl” group) structure with thedepicted ring as for example in the formula:

“Alkyl” is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof, inclusively. For example, “C₈alkyl” may refer to an n-octyl, iso-octyl, cyclohexylethyl, and thelike. Lower alkyl refers to alkyl groups of from one to six carbonatoms. Examples of lower alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and thelike. Higher alkyl refers to alkyl groups containing more than eightcarbon atoms. Exemplary alkyl groups are those of C₂₀ or below.Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groupsof from three to thirteen carbon atoms. Examples of cycloalkyl groupsinclude c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.In this application, alkyl refers to alkanyl, alkenyl, and alkynylresidues (and combinations thereof); it is intended to includecyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thus when analkyl residue having a specific number of carbons is named, allgeometric isomers having that number of carbons are intended to beencompassed; thus, for example, either “butyl” or “C₄ alkyl” is meant toinclude n-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2-yneradicals; and for example, “propyl” or “C₃ alkyl” each include n-propyl,propenyl, and isopropyl.

“Alkylene” refers to straight or branched chain divalent radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation and having from one to ten carbon atoms, for example,methylene, ethylene, propylene, n-butylene and the like. Alkylene is asubset of alkyl, referring to the same residues as alkyl, but having twopoints of attachment and, specifically, fully saturated. Examples ofalkylene include ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—),dimethylpropylene (—CH₂C(CH₃)₂CH₂—), and cyclohexylpropylene(—CH₂CH₂CH(C₆H₁₃).

“Alkoxy” or “alkoxyl” refers to the group —O-alkyl, for exampleincluding from one to eight carbon atoms of a straight, branched, cyclicconfiguration, unsaturated chains, and combinations thereof attached tothe parent structure through an oxygen atom. Examples include methoxy,ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.Lower-alkoxy refers to groups containing one to six carbons.

“Amino” refers to the group —NH₂, “Substituted amino,” refers to thegroup —N(H)R or —N(R)R where each R is independently selected from thegroup: optionally substituted alkyl, optionally substituted alkoxy,optionally substituted aryl, optionally substituted heterocyclyl, acyl,carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example,diethylamino, methylsulfonylamino, furanyl-oxy-sulfonamino.

Aryl” refers to aromatic six- to fourteen-membered carbocyclic ring, forexample, benzene, naphthalene, indane, tetralin, fluorene and the like,univalent radicals. As univalent radicals, the aforementioned ringexamples are named, phenyl, naphthyl, indanyl, tetralinyl, andfluorenyl.

“Fused-polycyclic” or “fused ring system” refers to a polycyclic ringsystem that contains bridged or fused rings; that is, where two ringshave more than one shared atom in their ring structures. In thisapplication, fused-polycyclics and fused ring systems are notnecessarily all aromatic ring systems. Typically, but not necessarily,fused-polycyclics share a vicinal set of atoms, for example naphthaleneor 1,2,3,4-tetrahydro-naphthalene. A Spiro ring system is not afused-polycyclic by this definition, but fused polycyclic ring systemsof the invention may themselves have Spiro rings attached thereto via asingle ring atom of the fused-polycyclic.

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.“Haloalkyl” and “haloaryl” refer generically to alkyl and aryl radicalsthat are substituted with one or more halogens, respectively. Thus,“dihaloaryl,” “dihaloalkyl,” “trihaloaryl” etc. refer to aryl and alkylsubstituted with a plurality of halogens, but not necessarily aplurality of the same halogen; thus 4-chloro-3-fluorophenyl is withinthe scope of dihaloaryl.

“Heteroatom” refers to O, S, N, or P.

“Heterocyclyl” refers to a stable three- to fifteen-membered ringradical that consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclyl radical may bea monocyclic, bicyclic or tricyclic ring system, which may include fusedor bridged ring systems as well as spirocyclic systems; and thenitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl radicalmay be optionally oxidized to various oxidation states. In a specificexample, the group —S(O)0-2-, refers to —S— (sulfide), —S(O)—(sulfoxide), and —SO2-(sulfone). For convenience, nitrogens,particularly but not exclusively, those defined as annular aromaticnitrogens, are meant to include their corresponding N-oxide form,although not explicitly defined as such in a particular example. Thus,for a compound of the invention having, for example, a pyridyl ring; thecorresponding pyridyl-N-oxide is meant to be included as anothercompound of the invention. In addition, annular nitrogen atoms may beoptionally quaternized; and the ring radical may be partially or fullysaturated or aromatic. Examples of heterocyclyl radicals include, butare not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl,quirtoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothieliyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.

“Heteroalicyclic” refers specifically to a non-aromatic heterocyclylradical. A heteroalicyclic may contain unsaturation, but is notaromatic.

“Heteroaryl” refers specifically to an aromatic heterocyclyl radical.

“Heterocyclylalkyl” refers to a residue in which a heterocyclyl isattached to a parent structure via one of an alkylene, alkylidene, oralkylidyne radical. Examples include (4-methylpiperazin-1-yl) methyl,(morpholin-4-yl) methyl, (pyridine-4-yl) methyl, 2-(oxazolin-2-yl)ethyl, 4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. Both theheterocyclyl, and the corresponding alkylene, alkylidene, or alkylidyneradical portion of a heterocyclylalkyl group may be optionallysubstituted. “Lower heterocyclylalkyl” refers to a heterocyclylalkylwhere the “alkyl” portion of the group has one to six carbons.“Heteroalicyclylalkyl” refers specifically to a heterocyclylalkyl wherethe heterocyclyl portion of the group is non-aromatic; and“heteroarylalkyl” refers specifically to a heterocyclylalkyl where theheterocyclyl portion of the group is aromatic Such terms may bedescribed in more than one way, for example, “lower heterocyclylalkyl”and “heterocyclyl C1-6alkyl” are equivalent terms.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that,with respect to any molecule described as containing one or moreoptional substituents, that only sterically practical and/orsynthetically feasible compounds are meant to be included. “Optionallysubstituted” refers to all subsequent modifiers in a term, for examplein the term “optionally substituted arylC1-8 alkyl,” optionalsubstitution may occur on both the “C1-8 alkyl” portion and the “aryl”portion of the molecule; and for example, optionally substituted alkylincludes optionally substituted cycloalkyl groups, which in turn aredefined as including optionally substituted alkyl groups, potentially adinfinitum. A list of exemplary optional substitution are listed below inthe definition of “substituted.”

“Substituted” alkyl, aryl, and heterocyclyl, refer respectively toalkyl, aryl, and heterocyclyl, wherein one or more (for example up toabout five, in another example, up to about three) hydrogen atoms arereplaced by a substituent independently selected from: optionallysubstituted alkyl (for example, fluoromethyl), optionally substitutedaryl (for example, 4-hydroxyphenyl), optionally substituted arylalkyl(for example, 1-phenyl-ethyl), optionally substituted heterocyclylalkyl(for example, 1-pyridin-3-yl-ethyl), optionally substituted heterocyclyl(for example, 5-chloro-pyridin-3-yl or 1-methyl-piperidin-4-yl),optionally substituted alkoxy, alkylenedioxy (for examplemethylenedioxy), optionally substituted amino (for example, alkylaminoand dialkylamino), optionally substituted amidino, optionallysubstituted aryloxy (for example, phenoxy), optionally substitutedarylalkyloxy (for example, benzyloxy), carboxy (—CO2H), carboalkoxy(that is, acyloxy or —OC(═O)R), carboxyalkyl (that is, esters or —CO2R),carboxamido, benzyloxycarbonylamino (CBZ-amino), cyano, acyl, halogen,hydroxy, nitro, sulfonyl, sulfonyl, sulfonyl, thiol, halogen, hydroxy,oxo, carbamyl, acylamino, and sulfonamido.

“Sulfanyl” refers to the groups: —S-(optionally substituted alkyl),—S-(optionally substituted aryl), and —S-(optionally substitutedheterocyclyl).

“Sulfonyl” refers to the groups: —S(O)—H, —S(O)-(optionally substitutedalkyl), —S(O)-optionally substituted aryl), and —S(O)-(optionallysubstituted heterocyclyl).

“Sulfonyl” refers to the groups: —S(O2)-H, —S(O2)-(optionallysubstituted alkyl), —S(O2)-optionally substituted aryl),—S(O2)-(optionally substituted heterocyclyl), —S(O2)-(optionallysubstituted alkoxy), —S(O2)-optionally substituted aryloxy, and—S(O2)-(optionally substituted heterocyclyloxy).

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

Compounds of the invention are named according to systematic applicationof the nomenclature rules agreed upon by the International Union of Pureand Applied Chemistry (IUPAC), International Union of Biochemistry andMolecular Biology (IUBMB), and the Chemical Abstracts Service (CAS).

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms, oxidized sulfur atoms orquaternized nitrogen atoms in their structure.

The compounds of the invention and their pharmaceutically acceptablesalts may exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. The compounds may also exist as geometricisomers. All such single stereoisomers, racemates and mixtures thereof,and geometric isomers are intended to be within the scope of thisinvention.

It is assumed that when considering generic descriptions of compounds ofthe invention for the purpose of constructing a compound, suchconstruction results in the creation of a stable structure. That is, oneof ordinary skill in the art would recognize that there cantheoretically be some constructs which would not normally be consideredas stable compounds (that is, sterically practical and/or syntheticallyfeasible, supra).

When a particular group with its bonding structure is denoted as beingbonded to two partners; that is, a divalent radical, for example,—OCH2-, then it is understood that either of the two partners may bebound to the particular group at one end, and the other partner isnecessarily bound to the other end of the particular group, unlessstated explicitly otherwise. Stated another way, divalent radicals arenot to be construed as limited to the depicted orientation, for example“—OCH2-” is meant to mean not only “—OCH2-” as drawn, but also “—CH2O—.”

With regard to various cyclic substituents, such as those within thescope of group W such as pyridinyl, when various positions of attachmentare possible, such as for pyridine (i.e., pyridin-2-yl, pyridin-3-yl,and pyridin-4-yl), all are within the scope of the present invention.

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. Enantiomers (R- andS-isomers) may be resolved by methods known to one of ordinary skill inthe art, for example by: formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, selective reaction of one enantiomer withan enantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature. Examples of isotopes suitable for inclusion in thecompounds of the invention include isotopes of hydrogen, such as 2H and3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine,such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, andsulphur, such as 35S. Certain isotopically-labelled compounds of formula(I), for example, those incorporating a radioactive isotope, are usefulin drug and/or substrate tissue distribution studies. The radioactiveisotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularlyuseful for this purpose in view of their ease of incorporation and readymeans of detection. Substitution with heavier isotopes such asdeuterium, i.e. 2H, may afford certain therapeutic advantages resultingfrom greater metabolic stability, for example, increased in vivohalf-life or reduced dosage requirements, and hence may be preferred insome circumstances. Substitution with positron emitting isotopes, suchas 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography(PET) studies for examining substrate receptor occupancy.Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagent in placeof the non-labeled reagent previously employed.

“Patient” for the purposes of the present invention includes humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. More specifically, the patient is a mammal, and in someembodiments, the patient is human.

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. The amount of a compound of the invention which constitutesa “therapeutically effective amount” will vary depending on thecompound, the disease state and its severity, the age of the patient tobe treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art having regardto his/her own knowledge and to this disclosure.

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the parent compound of the above formulae, for example,by hydrolysis in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about one and about six carbons)wherein the alkyl group is a straight or branched chain. Acceptableesters also include cycloalkyl esters and arylalkyl esters such as, butnot limited to benzyl. Examples of pharmaceutically acceptable amides ofthe compounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about one and about six carbons). Amides and esters of thecompounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; for example, biotransformation to a more polar molecule suchas by oxidation, reduction, or hydrolysis, or to a conjugate (seeGoodman and Gilman, “The Pharmacological Basis of Therapeutics” 8th Ed.,Pergamon Press, Gilman et al. (eds), 1990 for a discussion ofbiotransformation). As used herein, the metabolite of a compound of theinvention or its salt may be the biologically active form of thecompound in the body. In one example, a prodrug may be used such thatthe biologically active form, a metabolite, is released in vivo. Inanother example, a biologically active metabolite is discoveredserendipitously, that is, no prodrug design per se was undertaken. Anassay for activity of a metabolite of a compound of the presentinvention is known to one of skill in the art in light of the presentdisclosure.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

In addition, it is intended that the present invention cover compoundsmade either using standard organic synthetic techniques, includingcombinatorial chemistry or by biological methods, such as bacterialdigestion, metabolism, enzymatic conversion, and the like.

“Treatment” or a “treating” a condition as used herein is the practiceof any method, process, or procedure with the intent of halting,inhibiting, slowing or reversing the progression of a disease, disorderor condition, substantially ameliorating clinical symptoms of a diseasedisorder or condition, or substantially preventing the appearance ofclinical symptoms of a disease, disorder or condition, up to andincluding returning the diseased entity to its condition prior to thedevelopment of the disease.

“Treating” or “treatment” as used herein includes the treatment of acancer in a human, which cancer is characterized by abnormal cellularproliferation, and invasion and includes at least one of: (i) preventingthe disease-state from occurring in a human, in particular, when suchhuman is predisposed to the disease-state but has not yet been diagnosedas having it; (ii) inhibiting the disease-state, i.e., arresting itsdevelopment; and (iii) relieving the disease-state, i.e., causingregression of the disease-state. As is known in the art, adjustments forsystemic versus localized delivery, age, body weight, general health,sex, diet, time of administration, drug interaction and the severity ofthe condition may be necessary, and will be ascertainable with routineexperimentation by one of ordinary skill in the art.

All temperatures are in degrees Celsius (° C.). 20-25° C. denotes roomtemperature.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

Saline refers to an aqueous saturated sodium chloride solution.

Alcohol refers to ethyl alcohol.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance, and bioavailability.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

The invention further encompasses aspects in which a protecting group isadded to the compound. One skilled in the art would recognize thatduring the synthesis of complex molecules, one group on the disclosedcompound may happen to interfere with an intended reaction that includesa second group on the compound. Temporarily masking or protecting thefirst group encourages the desired reaction. Protection involvesintroducing a protecting group to a group to be protected, carrying outthe desired reaction, and removing the protecting group. Removal of theprotecting group may be referred to as deprotection. Examples ofcompounds to be protected in some syntheses include hydroxy groups,amine groups, carbonyl groups, carboxyl groups, and thiols.

A protecting group may result from any chemical synthesis thatselectively attaches a group that is resistant to certain reagents tothe chemical group to be protected without significant effects on anyother chemical groups in the molecule, remains stable throughout thesynthesis, and is removed through conditions that do not adversely reactwith the protected group, nor any other chemical group in the molecule.

Protecting groups, reagents that add those groups, preparations of thosereagents, protection and deprotection strategies under a variety ofconditions, including complex syntheses with mutually complementaryprotecting groups, are all well known in the art. Examples of all ofthese may be found in Green et al, Protective Groups in OrganicChemistry 2nd Ed., (Wiley 1991), and Harrison et al, Compendium ofSynthetic Organic Methods, Vols. 1-8 (Wiley, 1971-1996) both of whichhereby incorporated by reference in its entirety.

Racemates, individual enantiomers, or diasteromers of the disclosedcompound are prepared by specific synthesis or resolution through knownmethods. For example, the disclosed compound may be resolved into itenantiomers by the formation of diasteromeric pairs through saltformation using an optically active acid. Enantiomers are fractionallycrystallized and the free base regenerated. In another example,enantiomers may be separated by chromatography. Such chromatography isany appropriate method that is appropriate to separate enantiomers suchas HPLC on a chiral column as is known to those skilled in the art.

Cancer cells include any cells derived from a tumor, neoplasm, cancer,precancer, cell line, or any other source of cells that are ultimatelycapable of potentially unlimited expansion and growth. Cancer cells maybe derived from naturally occurring sources or may be artificiallycreated. Cancer cells may also be capable of invasion into other tissuesand metastasis when placed into an animal host. Cancer cells furtherencompass any malignant cells that have invaded other tissues and/ormetastasized. One or more cancer cells in the context of an organism mayalso be called a cancer, tumor, neoplasm, growth, malignancy, or anyother term used in the art to describe cells in a cancerous state.

Expansion of a cancer cell includes any process that results in anincrease in the number of individual cells derived from a cancer cell.Expansion of a cancer cell may result from mitotic division,proliferation, or any other form of expansion of a cancer cell, whetherin vitro or in vivo. Expansion of a cancer cell further encompassesinvasion and metastasis. A cancer cell may be in physical proximity tocancer cells from the same clone or from different clones that may ormay not be genetically identical to it. Such aggregations may take theform of a colony, tumor or metastasis, any of which may occur in vivo orin vitro. Slowing the expansion of the cancer cell may be brought abouteither by inhibiting cellular processes that promote expansion or bybringing about cellular processes that inhibit expansion. Processes thatinhibit expansion include processes that slow mitotic division andprocesses that promote cell senescence or cell death. Examples ofspecific processes that inhibit expansion include capsase dependent andindependent pathways, autophagy, necrosis, apoptosis, and mitochondrialdependent and independent processes.

Treatment is contemplated in living entities including but not limitedto mammals (particularly humans) as well as other mammals includelivestock (horses, cattle, sheep, pigs) and other animals generally bredfor domesticated companion animals such as dogs and cats.

Compounds

As indicated previously, in one aspect, the invention is directed to acompound of formula III

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of formula III, Q is CH.

In some embodiments, R₁ is —F, —Cl, or —Br. More particularly, R₁ is—Cl.

In some embodiments, R₃ is —OR₃₋₁. More particularly, R₃₋₁ is —Cl.

In some embodiments, R₄ and R₅ are —H.

In some embodiments RN is —H.

When X₁₋₂ and X₁₋₃ are taken together with the attached nitrogen atom toform a monocyclic structure consisting of four through seven atomsselected from the group consisting of carbon and nitrogen, the cyclicstructure can be either saturated like piperazinyl or aromatic likepyridinyl.

Thus, in some embodiments, the monocyclic structure be selected from thegroup consisting of piperazin-1-yl optionally substituted in the4-position with C1-C3 alkyl, —CO—(C₁-C₃ alkyl), —SO₂—H, or SO₂—(C₁-C₃)alkyl; piperidin-1-yl and piperidin-4-yl both optionally substitutedwith one —F, —Cl, C₁-C₃ alkyl, —CO—(C₁-C₃ alkyl), —SO₂—H, or—SO₂—(C1-C3) alkyl; and pyrrolidin-1-yl, pyrrolinin-2-yl, andpyrrolidin-3-yl all optionally substituted with one —F, —Cl, C1-C₃alkyl, —CO—(C₁-C₃ alkyl), —SO₂—H, or SO2-(C₁-C₃) alkyl.

More particularly, X₁₋₂ and X₁₋₃ are cyclized to form pyrrolidin-1-yl,N-(1-methylpyrrolidin-3-yl), N-(4-methylpiperazin-1-yl), andN-(1ethylpiperadin-4-yl).

Also, when W is a cyclic structure of three through seven atomsconsisting of carbon, nitrogen, and sulfur, the cyclic structure beselected from the group consisting of phenyl, thiazolyl, pyridinyl, andC₃-C₇ cycloalkyl.

In some embodiments, the compound of formula HI is a compound selectedfrom Examples 5, 7, 10, and 16.

One embodiment of a compound of formula III is a compound of formulaIII(a):

or a pharmaceutically acceptable salt thereof, wherein:

Q₁ is selected from the group consisting of CH and N;

R₁₁ is selected from the group consisting of H, F, Cl, Br, and C₁₋₃haloalkyl;

R₁₂ is selected from the group consisting of H, F, Cl, Br, OH, C₁₋₃alkyl, C₁₋₃ haloalkyl, and C₁₋₃ alkoxy;

R₁₃ is selected from the group consisting of H, C₁₋₃ alkyl, and C₁₋₃haloalkyl;

R₁₄ is selected from the group consisting of optionally substituted 5-or 6-membered cycloalkyl or heterocycloalkyl, optionally substituted

optionally substituted

andoptionally substituted

wherein the alkylene chains may be optionally substituted with up to 3R₁₈;

R₁₅ and R₁₆ are each independently selected from the group consisting ofH, alkyl, cycloalkyl, alkoxy, alkylamino, and sulfonyl;

or R₁₅ and R₁₆ may be joined together to form an optionally substituted5- or 6-membered cycloalkyl or heterocycloalkyl;

R₁₇ is selected from the group consisting of H, alkyl, cycloalkyl,alkoxy, alkylamino, and sulfonyl; and

R₁₈ is selected from the group consisting of H, alkyl, cycloalkyl,alkoxy, alkylamino, and sulfonyl.

In one embodiment of the compound of formula III(a), Q₁ is CH.

In another embodiment, Q₁ is N.

In one embodiment, R₁₁ is H, F, or Cl.

More particularly, R₁₁ is H.

In another embodiment, R₁₁ is F.

In yet another embodiment, R₁₁ is Cl.

In one embodiment, R₁₂ is H, F, Cl, OH, or C₁₋₃ alkoxy;

More particularly, R₁₂ is F or C₁₋₃ alkoxy.

More particularly, R₁₂ is F.

In another embodiment, R₁₂ is C₁₋₃ alkoxy.

More particularly, R₁₂ is methoxy.

In one embodiment, R₁₃ is H.

In another embodiment, R₁₃ is C₁₋₃ alkyl.

More particularly, R₁₃ is methyl.

In one embodiment, R₁₁ is C₁, and R₁₂ is methoxy.

In another embodiment, Q₁ is N, and R₁₂ is methoxy.

In another embodiment, Q₁ is N, and R₁₂ is H.

In another embodiment, R₁₁ is Br, and R₁₂ is methoxy.

In another embodiment, R₁₁ is F, and R₁₂ is methoxy.

In another embodiment, Q₁ is CH, and R₁₂ is Cl or F.

In one embodiment, R₁₃ is H, and Q₁ is CH.

In another embodiment, R₁₁ is CI, and R₁₃ is H.

In any of the above embodiments of a compound of formula III(a) providedabove, R₁₄ is an optionally substituted 5- or 6-membered cycloalkyl orheterocycloalkyl,

wherein the alkylene chains may be optionally substituted with up to 3R₁₈.

In some embodiments, R₁₄ is an optionally substituted 5- or 6-memberedheterocycloalkyl.

More particularly, R₁₄ is

In some embodiments, R₁₄ is optionally substituted

wherein the alkylene chain may be optionally substituted with up to 3R₁₈.

More particularly, R₁₄ is

In some embodiments, R₁₄ is optionally substituted

wherein the alkylene chain may be optionally substituted with up to 3R₁₈.

More particularly, in some embodiments, R₁₄ is

In some embodiments, R₁₄ is optionally substituted

wherein the alkylene chain may be optionally substituted with up to 3R₁₈.

More particularly, R₁₄ is

In another aspect, the invention is directed to a compound of formula V

or a pharmaceutically acceptable salt thereof.

In some embodiments, R₁ is —F, —Cl, and —Br. More particularly, R₁ is—Cl.

In some embodiments, R_(N) is —H. In some embodiments, X₁₋₂ and X₁₋₃ aretaken together with the attached nitrogen atom to form a monocyclicstructure consisting of four through seven atoms selected from the groupconsisting of carbon, nitrogen and oxygen. In some embodiments, themonocyclic structure be selected from the group consisting of where X₁₋₂and X₁₋₃ are cyclized to form a cyclic structure selected from the groupconsisting of piperazin-1-yl optionally substituted in the 4-positionwith C₁-C₃ alkyl, —CO—(C₁-C₃ alkyl), —SO₂—H, or —SO₂—(C₁-C₃) alkyl;piperidin-1-yl and piperidin-4-yl both optionally substituted with one—F, —Cl, C₁-C₃ alkyl, —CO—(C₁-C₃ alkyl), —SO₂—H, or —SO₂—(C₁-C₃) alkyl;morpholin-1-yl optionally substituted with one —F, —Cl, C₁-C₃ alkyl,—CO—(C₁-C₃ alkyl), —SO₂—H, or —SO₂—(C₁-C₃) alkyl; pyrrolidin-1-yl,pyrrolinin-2-yl, and pyrrolidin-3-yl all optionally substituted with one—F, —Cl, C₁-C₃ alkyl, —CO—(C₁-C₃ alkyl), —SO₂—H, or —SO₂—(C₁-C₃).

More particularly, X₁₋₂ and X₁₋₃ are cyclized to form pyrrolidin-1-yl,N-(1-methylpyrrolidin-3-yl), N-(4-methylpiperazin-1-yl), and N-(1ethylpiperadin-4-yl).

Also, when W is a cyclic structure of three through seven atomsconsisting of carbon, nitrogen, and sulfur, that the cyclic structure beselected from the group consisting of phenyl, thiazolyl, pyridinyl, andC₃-C₇ cycloalkyl.

One embodiment of a compound of formula V is a compound of formula V(a):

or a pharmaceutically acceptable salt thereof, wherein:

R₂₁ is selected from the group consisting of H, F, Cl, Br, and C₁₋₃haloalkyl;

R₂₂ is selected from the group consisting of H, C₁₋₃ alkyl, and C₁₋₃haloalkyl;

R₂₃ is selected from the group consisting of an optionally substituted5- or 6-membered cycloalkyl or heterocycloalkyl, optionally substituted

optionally substituted

and optionally substituted

wherein the alkylene chains may be optionally substituted with up to 3R₁₈;

R₁₅ and R₁₆ are each independently selected from the group consisting ofH, alkyl, cycloalkyl, alkoxy, alkylamino, and sulfonyl;

or R₁₅ and R₁₆ may be joined together to form an optionally substituted5- or 6-membered cycloalkyl or heterocycloalkyl;

R₁₇ is selected from the group consisting of H, alkyl, cycloalkyl,alkoxy, alkylamino, and sulfonyl; and

R₁₈ is selected from the group consisting of H, alkyl, cycloalkyl,alkoxy, alkylamino, and sulfonyl.

In one embodiment, R₂₁ is H, F, or Cl.

More particularly, R₂₁ is H.

In another embodiment, R₂₁ is F.

In yet another embodiment, R₂₁ is Cl.

In one embodiment, is H.

In another embodiment, R₂₂ is C₁₋₃ alkyl.

More particularly, R₂₂ is methyl.

In one embodiment, R₂₁ is Cl, and R₂₂ is H

In another embodiment, R₂₁ is Br, and R₂₂ is H.

In another embodiment, R₂₁ is F, and R₂₂ is methyl.

In any of the above embodiments of a compound of formula III(a) providedabove, R₂₂ is an optionally substituted 5- or 6-membered cycloalkyl orheterocycloalkyl,

wherein the alkylene chains may be optionally substituted with up to 3R₁₈.

In some embodiments, R₂₂ is optionally substituted 5- or 6-memberedheterocycloalkyl.

More particularly, R₂₂ is

In some embodiments, R₂₂ is optionally substituted

wherein the alkylene chain may be optionally substituted with up to 3R₁₈.

More particularly, R₂₂ is

In some embodiments, R₂₂ is optionally substituted

wherein the alkylene chain may be optionally substituted with up to 3R₁₈.

More particularly, in some embodiments, R₂₂ is

In some embodiments, R₂₂ is optionally substituted

wherein the alkylene chain may be optionally substituted with un to 3R₁₈.

More particularly, R₂₂ is

In another embodiment of a compound of formula V, the compounds are offormula V(b)

or a pharmaceutically acceptable salt thereof, wherein the variables andembodiments are as defined above for a compound of formula V(a).

In one aspect, the compound of the invention is selected from thecompounds provided in Table 1:

TABLE 1 Example Structure Name 1

6-Chloro-N-(1-ethylpiperidin-4- yl)-2-methoxyacridin-9-amine 2

6-Chloro-N-(2-(2- (diethylamino)ethoxy)ethyl)-2- methoxyacridin-9-amine3

6-Chloro-2-methoxy-N-(4- methoxybutyl)acridin-9-amine 4

6-Chloro-2-methoxy-N-(4- (pyrrolidin-1-yl)butyl)acridin- 9-amine 5

N¹-tert-butyl-N⁴-(6-chloro-2- methoxyacridin-9-yl)butane- 1,4-diamine 6

N-(4-(6-Chloro-2- methoxyacridin-9- ylamino)butyl)-N-ethylmethanesulfonamide 7

6-Chloro-2-methoxy-N-(4-(4- methylpiperazin-1- yl)butyl)acridin-9-amine8

3-Chloro-N-(1-ethylpiperidin- 4-yl)acridin-9-amine 9

N-(4-(6-Chloro-2- methoxyacridin-9- ylamino)butyl)-N- ethylacetamide 10

N¹-(6-Chloro-2- methoxyacridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine 11

6-Chloro-2-methoxy-N-(2- methoxyethyl)acridin-9-amine 12

N¹-(6-Chloro-2- methoxyacridin-9-yl)-N⁴- cyclopropyl-N⁴-ethylbutane-1,4-diamine 13

N¹-(6-Chloro-2- methoxyacridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴-ethylbutane-1,4-diamine 14

N¹-(6-Chloro-2- methoxyacridin-9-yl)-N⁴,N⁴- diethyl-N¹-methylbutane-1,4-diamine 15

N-(1-Ethylpiperidin-4- yl)acridin-9-amine 16

6-Chloro-N-(1-ethylpiperidin- 4-yl)-2-fluoroacridin-9-amine 17

6-Chloro-2-fluoro-N-(2-(4- methylpiperazin-1- yl)ethyl)acridin-9-amine18

N-(1-Ethylpiperidin-4-yl)-6- fluoro-2-methoxyacridin-9- amine 19

3-Chloro-N-(2-(4- methylpiperazin-1- yl)ethyl)acridin-9-amine 20

6-Fluoro-2-methoxy-N-(2-(4- methylpiperazin-1- yl)ethyl)acridin-9-amine21

6-Chloro-2-methoxy-N-(2-(4- methylpiperazin-1- yl)ethyl)acridin-9-amine22

6-Chloro-2-methoxy-N-(1- methylpiperidin-4-yl)acridin- 9-amine 23

7-Chloro-2-methoxy-N-(2-(4- methylpiperazin-1- yl)ethyl)benzo[b][1,5]naphthyridin-10-amine 24

7-Chloro-N-(1-ethylpiperidin- 4-yl)-2-methoxybenzo[b][1,5]naphthyridin-10-amine 25

N-(1-Ethylpiperidin-4-yl)-2- methoxyacridin-9-amine 26

6-Chloro-N-(1-ethylpiperidin- 4-yl)-1,2,3,4- tetrahydroacridin-9-amine27

6-Chloro-N-(2-(4- methylpiperazin-1-yl)ethyl)-1,2,3,4-tetrahydroacridin-9- amine 28

6-Chloro-2-methoxy-N-(1- methylpyrrolidin-3-yl)acridin- 9-amine 29

6-Chloro-2-fluoro-N-(1-(4- methylpiperazin-1-yl)propan-2-yl)acridin-9-amine 30

N¹-(acridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴- methylbutane-1,4-diamine31

N¹-(cyclopropylmethyl)-N⁴-(2- fluoroacridin-9-yl)-N¹-methylbutane-1,4-diamine 32

N¹-(2-chloroacridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine 33

N¹-(cyclopropylmethyl)-N⁴-(2- methoxyacridin-9-yl)-N¹-methylbutane-1,4-diamine 34

N¹-(6-bromo-2- methoxyacridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine 35

N¹-(cyclopropyl-methyl)-N⁴- (6-fluoro-2-methoxyacridin-9-yl)-N¹-methylbutane-1,4- diamine 36

N¹-(6-chloro-2-fluoroacridin- 9-yl)-N⁴-(cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine 37

N¹-(cyclopropylmethyl)-N⁴- (2,6-dichloroacridin-9-yl)-N¹-methylbutane-1,4-diamine 38

N¹-(3-chloroacridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine 39

7-chloro-10-(4-((cyclopropyl- methyl)(methyl)amino)butylamino)benzo[b][1,5]naphthyridin- 2-ol 40

N¹-(7- chlorobenzo[b][1,5]naphthyridin- 10-yl)-N⁴-(cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine 41

N¹-(cyclopropylmethyl)-N⁴-(2,7- dichlorobenzo[b][1,5]naphthyridin-10-yl)-N¹-methylbutane-1,4- diamine 42

N¹-(7-chloro-2-methoxybenzo[b] [1,5]naphthyridin-10-yl)-N⁴-(cyclopropylmethyl)-N⁴- methylbutane-1,4-diamine 43

N¹-(6-chloro-1,2,3,4- tetrahydroacridin-9-yl)-N⁴-(cyclopropylmethyl)-N⁴- methylbutane-1,4-diamine 44

N¹-(6-chloro-2,3-dihydro-1H- cyclopenta[b]quinolin-9-yl)-N⁴-(cyclopropylmethyl)-N⁴- methylbutane-1,4-diamine 45

N¹-(6-chloro-2-methoxyacridin- 9-yl)-N³-(cyclopropylmethyl)-N³-methylpropane-1,3-diamine 46

N¹-(6-chloro-2-methoxyacridin- 9-yl)-N²-(cyclopropylmethyl)-N²-methylethane-1,2-diamine 47

N⁴-(6-chloro-2-methoxyacridin- 9-yl)-N¹-(cyclopropylmethyl)-N¹-methylpentane-1,4-diamine 48

N⁴-(6-chloro-2-methoxyacridin- 9-yl)-N¹-(cyclopropylmethyl)-N¹-methylhexane-1,4-diamine 49

N⁴-(6-chloro-2-methoxyacridin- 9-yl)-N¹-(cyclopropylmethyl)-5-methoxy-N¹-methylpentane-1,4- diamine 50

N¹-(6-chloro-2-methoxyacridin- 9-yl)-N⁴-(cyclopropylmethyl)-N⁴-(2-methoxyethyl)butane-1,4- diamine 51

2-((4-(6-chloro-2-methoxyacridin- 9-ylamino)butyl)(cyclopropylmethyl)amino)ethanol 52

N-(4-(6-chloro-2-methoxyacridin-9- ylamino)butyl)-N-(cyclopropylmethyl)acetamide 53

N-(4-(6-chloro-2-methoxyacridin-9- ylamino)butyl)-N- (cyclopropylmethyl)methanesulfonamide 54

N¹-(6-chloro-2-methoxyacridin-9- yl)-N⁴-(cyclopropylmethyl)butane-1,4-diamine 55

6-chloro-N-(4-(cyclopropylmethoxy) butyl)-2-methoxyacridin-9-amine 56

N¹-(6-chloro-2-methoxyacridin-9- yl)-N⁴-cyclopropyl-N⁴-methylbutane-1,4-diamine 57

6-chloro-2-fluoro-N-(1- morpholinopropan-2- yl)acridin-9-amine 58

7-Chloro-2-methoxy-N-(1-(4- methylpiperazin-1-yl)propan-2-yl)benzo[b][1,5]naphthyridin- 10-amine 59

7-Chloro-2-methoxy-N-(1- morpholinpropan-2-yl)benzo[b][1,5]naphthyridin- 10-amine 60

6-Chloro-N-(1-(4-methylpiperazin- 1-yl)propan-2-yl)-1,2,3,4-tetrahydroacridin-9-amine 61

6-Chloro-N-(1-morpholinopropan- 2-yl)-1,2,3,4-tetrahydroacridin-9- amine62

6-Chloro-N-(4-(4-methylpiperazin- 1-yl)butan-2-yl)-1,2,3,4-tetrahydroacridin-9-amine 63

6-Chloro-N-(4-morpholinobutan-2- yl)-1,2,3,4-tetrahydroacridin-9-amine64

6-chloro-2-methoxy-N-(4- morpholinobutyl)acridin-9-amine

The compounds of formulas III and V are amines and, as such, form saltswhen reacted with acids. Thus, pharmaceutically acceptable salts ofcompounds of formulas HI and V are included within the scope of thisinvention. Pharmaceutically acceptable salts include salts of bothinorganic and organic acids. The pharmaceutically acceptable salts arepreferred over the corresponding free amines since they producecompounds that are more water soluble and more crystalline.Pharmaceutically acceptable salts are any salt which retains theactivity of the parent compound and does not impart any deleterious orundesirable effect on the subject to whom it is administered and in thecontext in which it is administered. The preferred pharmaceuticallyacceptable salts include salts of the following acids acetic, aspartic,benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric,calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic,edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic,glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic,hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic,lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic,methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic,p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogenphosphoric, dihydrogen phosphoric, phthalic, polygalactouronic,propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic,sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic. Forother acceptable salts, see Int. J. Pharm., 33, 201-217 (1986) and J.Pharm. Sci., 66(1), 1, (1977).

In some aspects of the invention the disclosed compound, is in the formof a pharmaceutically acceptable salt. Pharmaceutically acceptable saltsinclude any salt derived from an organic or inorganic acid. Examples ofsuch salts include but are not limited to the following: salts ofhydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, andsulphuric acid. Organic acid addition salts include, for example, saltsof acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonicacid, citric acid, 2-(4-chlorophenoxy)-2-methylpropionic acid,1,2-ethanedisulphonic acid, ethanesulphonic acid,ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonicacid, gluconic acid, glutamic acid, N-glycolylarsanilic acid,4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl) benzoicacid,1-hydroxy-2-naphthoicacid, 3-hydroxy-2-naphthoic acid,2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuricacid, maleic acid, malic acid, mandelic acid, methanesulphonic acid,methyl sulpuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoicacid, pantothenic acid, phosphanilic acid ((4-aminophenyl) phosphoricacid), picric acid, salicylic acid, stearic acid, succinic acid, tannicacid, tartaric acid, terephthalic acid, p-toluenesulphonic acid,10-undecenoic acid, or any other such acid now known or yet to bedisclosed. It will be appreciated by one skilled in the art that suchpharmaceutically acceptable salts may be used in the formulation of apharmacological composition. Such salts may be prepared by reacting thedisclosed compounds with a suitable acid in a manner known by thoseskilled in the art.

Pharmaceutically acceptable anion salts include, but are not limited to,salts of the following acids: methanesulfonic, hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric,fumaric, maleic, CH₃—(CH₂)_(n)—COOH where n is 0 through 4, andHOOC—(CH₂)N—COOH where n is as defined above.

Processes for Making Compounds of Formula III or V

The compounds of formula III or V are prepared from known compounds bymethods known to those skilled in the art, Thus a compound of formulaIII is prepared from the corresponding compound of formula I by couplingwith an amine of formula II, as depicted in Scheme 1.

Similarly, the compound of formula V is prepared by from thecorresponding compound of formula IV by coupling with an amine offormula II, as depicted in Scheme 2:

To the extent that some of the halides of formula I, the amines offormula II, and the halides of formula IV are not known compounds, theycan be readily prepared from known compounds by methods known to thoseskilled in the art.

More specifically, the halides of formulas I and IV are heated to about100° C. in a solvent like phenol. To this mixture, the desired amine(II) is added, and the mixture is kept at about 100° C. for about 5hours. The mixture is cooled, diluted with a solvent such asdichloromethane, and is worked up as is known to those skilled in theart. Example 1 illustrates the process.

Pharmaceutical Compositions and Formulations

In another aspect, the invention further provides pharmaceuticalcompositions that include the compounds of formula III or V as theactive pharmaceutical ingredient(s). Such pharmaceutical compositionsmay take any physical form necessary depending on a number of factorsincluding the desired method of administration and the physicochemicaland stereochemical form taken by the compound or pharmaceuticallyacceptable salts of the compound. The concept of a pharmaceuticalcomposition including compounds of formulas III and V also encompassesthe compounds or a pharmaceutically acceptable salt thereof without anyother additive. The physical form of the invention may affect the routeof administration, and one skilled in the art would know to choose aroute of administration that takes into consideration both the physicalform of the compound and the disorder to be treated. Pharmaceuticalcompositions are prepared using known methods.

A pharmaceutical composition may include a second effective compound ofa distinct chemical formula from the compounds of formula III or V. Thissecond effective compound may have the same or a similar moleculartarget or it may act upstream or downstream of the molecular target ofthe compounds of formula III or V with regard to one or more biochemicalpathways.

Pharmaceutical compositions including the compounds of formula III or Vinclude materials capable of modifying the physical form of a dosageunit. In one example, the composition may a material that forms acoating that surrounds and/or contains the pharmaceutical composition.Materials that may be used in such a coating, include, for example,sugar, shellac, gelatin, or any other inert coating agent.

Pharmaceutical compositions of the compounds of formula III or V can beprepared as a gas or aerosol. Aerosols encompass a variety of systemsincluding colloids and pressurized packages. Delivery of a compositionin this form may include propulsion of a pharmaceutical compositionincluding the disclosed compound through use of liquefied gas or othercompressed gas or by a suitable pump system. Aerosols may be deliveredin single phase, bi-phasic, or tri-phasic systems.

In some aspects of the invention, the compounds of formula III or V ofthe pharmaceutical composition are in the form of a solvate, Suchsolvates are produced by the dissolution of the disclosed compound in apharmaceutically acceptable solvent. Pharmaceutically acceptablesolvents include any mixtures of more than one solvent. Such solventsmay include propan-1-ol, ethyl oleate, ethyl lactate, ethylene oxide,water, ethanol, and any other solvent that delivers a sufficientquantity of the disclosed compound to treat the affliction withoutserious complications arising from the use of the solvent in patients.

Pharmaceutical compositions also include a pharmaceutically acceptablecarrier. Carriers include any substance that may be administered withthe compounds of formula III or V with the intended purpose offacilitating, assisting, or helping the administration or other deliveryof the compound. Carriers include any liquid, solid, semisolid, gel,aerosol or anything else that may be combined with the active compoundto aid in its administration. Examples of carriers include diluents,adjuvants, excipients, water, and oils (including petroleum, animal,vegetable or synthetic oils). Such carriers include particulates such asa tablet or powder, liquids such as an oral syrup or injectable liquid,and inhalable aerosols. Further examples include saline, gum acacia,gelatin, starch paste, talc, keratin, colloidal silica, and urea. Suchcarriers may further include binders such as ethyl cellulose,carboxymethylcellulose, microcrystalline cellulose, or gelatin;excipients such as starch, lactose or dextrins; disintegrating agentssuch as alginic acid, sodium alginate, Primogel, and corn starch;lubricants such as magnesium stearate or Sterotex; glidants such ascolloidal silicon dioxide; sweetening agents such as sucrose orsaccharin, a flavoring agent such as peppermint, methyl salicylate ororange flavoring, or coloring agents. Further examples of carriersinclude polyethylene glycol, cyclodextrin, oils, or any other similarliquid carrier that may be formulated into a capsule. Still furtherexamples of carriers include sterile diluents such as water forinjection, saline solution, physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordigylcerides, polyethylene glycols, glycerin, cyclodextrin, propyleneglycol or other solvents; antibacterial agents such as benzyl alcohol ormethyl paraben; antioxidants such as ascorbic acid or sodium bisulfate;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose, thickening agents,lubricating agents, and coloring agents.

The pharmaceutical composition can take any of a number of formulationsdepending on the physicochemical form of the composition and the type ofadministration. Such forms include solutions, suspensions, emulsions,tablets, pills, pellets, capsules, capsules including liquids, powders,sustained-release formulations, directed release formulations,lyophylates, suppositories, emulsions, aerosols, sprays, granules,powders, syrups, or elixirs. Examples include local infusion duringsurgery; topical application, by local injection; by a catheter; by asuppository; or by an implant. Administration can be by direct injectionat the site (or former site) of a cancer, tumor, or precancerous tissueor into the central nervous system by any suitable route, includingintraventricular and intrathecal injection. Intraventricular injectionmay be facilitated by an intraventricular catheter, for example,attached to a reservoir, such as an Ommaya reservoir. Pulmonaryadministration may be achieved by any of a number of methods known inthe art. Examples include use of an inhaler or nebulizer, formulationwith an aerosolizing agent, or via perfusion in a fluorocarbon orsynthetic pulmonary surfactant. The compound of formula III or V can bedelivered in the context of a vesicle such as a liposome or any othernatural or synthetic vesicle.

A pharmaceutical composition formulated so as to be administered byinjection may be prepared by dissolving the disclosed compound withwater so as to form a solution. In addition, a surfactant may be addedto facilitate the formation of a homogeneous solution or suspension.Surfactants include any complex capable of non-covalent interaction withthe active ingredient so as to facilitate dissolution or homogeneoussuspension of the compound.

Pharmaceutical compositions can be prepared in a form that facilitatestopical or transdermal administration. Such preparations may be in theform of a solution, emulsion, ointment, gel base, transdermal patch oriontophoresis device. Examples of bases used in such compositionsinclude opetrolatum, lanolin, polyethylene glycols, beeswax, mineraloil, diluents such as water and alcohol, and emulsifiers andstabilizers, thickening agents, or any other suitable base now known oryet to be disclosed.

In some embodiments, the compounds of formula III or V may be used incombination with additional agents. More particularly, the additionalagent may be temozolomide or PLX-4032.

Examples of pharmaceutical compositions that may be used in combinationwith the compounds of formula III or V include nucleic acid bindingcompositions such as cis-diamminedichloro platinum (II) (cisplatin),doxorubicin, 5-fluorouracil, taxol, and topoisomerase inhibitors such asetoposide, teniposide, irinotecan and topotecan. Still otherpharmaceutical compositions include antiemetic compositions such asmetoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine,thioproperazine and tropisetron.

Still other examples of pharmaceutical compositions that can be used incombination with a pharmaceutical composition of the compounds offormula III or V are hematopoietic colony stimulating factors. Examplesof hematopoietic colony stimulating factors include, but are not limitedto, filgrastim, sargramostim, molgramostim and epoietin alfa.Alternatively, the pharmaceutical composition of the compounds offormula III or V can be used in combination with an anxiolytic agent.Examples of anxiolytic agents include, but are not limited to,buspirone, and benzodiazepines such as diazepam, lorazepam, oxazapam,chlorazepate, clonazepam, chlordiazepoxide and alprazolam.

Pharmaceutical compositions that may be used in combination withpharmaceutical compositions that include the compounds of formula III orV can include analgesic agents. Such agents may be opioid or non-opioidanalgesic. Non-limiting examples of opioid analgesics include morphine,heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon,apomorphine, normorphine, etorphine, buprenorphine, meperidine,lopermide, anileridine, ethoheptazine, piminidine, betaprodine,diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil,levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine,methadone, isomethadone and propoxyphene. Suitable non-opioid analgesicagents include, but are not limited to, aspirin, celecoxib, rufecoxib,dicloimac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen,ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid,nabumetone, naproxen, piroxicam, sulindac or any other analgesic.

In other aspects of the invention, pharmaceutical compositions of thecompounds of formula III or V can be used in combination with a methodthat involves treatment of cancer ex vivo. One example of such atreatment is an autologous stem cell transplant. In this method, adiseased entity's autologous hematopoietic stem cells are harvested andpurged of all cancer cells. A therapeutic amount of a pharmaceuticalcomposition including the compounds of formula III or V can then beadministered to the patient prior to restoring the entity's bone marrowby addition of either the patient's own or donor stem cells.

Methods

Another aspect is a method treating a condition or disease, comprisingadministering to a subject in need of such treatment a compound orpharmaceutical composition of a compound of formula III or V.

In some embodiments, the disorder or disease is cancer,neurodegenerative disorders, autoimmune disorders, cardiovasculardisorders, metabolic disorders, hamartoma syndrome, genetic muscledisorders, and myopathies.

In another aspect, the invention provides a method of treating cancer,comprising administrating to a patient in need of such treatment (e.g.,a human patient) a compound of formula II or V, a pharmaceutically saltthereof or a pharmaceutical composition comprising a compound of formulaIII or V.

Cancers that may be treated by pharmaceutical compositions including thecompounds of formula III or V either alone or in combination withanother treatment modality include solid tumors such as fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer,kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovariancancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer,nasal cancer, throat cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms'tumor, cervical cancer, uterinecancer, testicular cancer, small cell lung carcinoma, bladder carcinoma,lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme,astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skincancer, melanoma, neuroblastoma, and retinoblastoma.

Addition of a pharmaceutical composition to cancer cells includes allactions by which an effect of the pharmaceutical composition on thecancer cell is realized. The type of addition chosen will depend uponwhether the cancer cells are in vivo, ex vivo, or in vitro, the physicalor chemical properties of the pharmaceutical composition, and the effectthe composition is to have on the cancer cell. Nonlimiting examples ofaddition include addition of a solution including the pharmaceuticalcomposition to tissue culture media in which in vitro cancer cells aregrowing; any method by which a pharmaceutical composition may beadministered to an animal including intravenous, per os, parenteral, orany other of the methods of administration; or the activation orinhibition of cells that in turn have effects on the cancer cells suchas immune cells (e.g. macophages and CD8+ T cells) or endothelial cellsthat may differentiate into blood vessel structures in the process ofangiogenesis or vasculogenesis.

Determination of an effective amount of the compounds of formula III orV is within the capability of those skilled in the art, especially inlight of the detailed disclosure provided herein. The effective amountof a pharmaceutical composition used to effect a particular purpose aswell as its toxicity, excretion, and overall tolerance is determined incell cultures or animals by pharmaceutical and toxicological procedures.One example is the determination of the IC50 (half maximal inhibitoryconcentration) of the pharmaceutical composition in vitro in cell linesor target molecules. Another example is the determination of the LD50(lethal dose causing death in 50% of the tested animals) of thepharmaceutical composition in experimental animals. The exact techniquesused in determining an effective amount will depend on factors such asthe type and physical/chemical properties of the pharmaceuticalcomposition, the property being tested, and whether the test is to beperformed in vitro or in vivo. The determination of an effective amountof a pharmaceutical composition is well known to one of skill in the artwho will use data obtained from any tests in making that determination.Determination of an effective amount of the compounds of formula III orV for addition to a cancer cell also includes the determination of aneffective therapeutic amount, including the formulation of an effectivedose range for use in vivo, including in humans.

The toxicity and therapeutic efficacy of a pharmaceutical compositionmay be determined by standard pharmaceutical procedures in cell culturesor animals. Examples include the determination of the IC50 (the halfmaximal inhibitory concentration) and the LD50 (lethal dose causingdeath in 50% of the tested animals) for a subject compound. The dataobtained from these cell culture assays and animal studies can be usedin formulating a range of dosage for use in human. The dosage may varydepending upon the dosage form employed and the route of administrationutilized.

The effective amount of compound of formula III or V to result in theslowing of expansion of the cancer cells would preferably result in aconcentration at or near the target tissue that is effective in slowingcellular expansion in neoplastic cells, but have minimal effects onnon-neoplastic cells, including non-neoplastic cells exposed toradiation or recognized chemotherapeutic chemical agents. Concentrationsthat produce these effects can be determined using, for example,apoptosis markers such as the apoptotic index and/or capsase activitieseither in vitro or in vivo.

The addition of a therapeutically effective amount of the compounds offormula III or V encompasses any method of dosing of a compound. Dosingof the disclosed compound may include single or multiple administrationsof any of a number of pharmaceutical compositions that include thedisclosed compound as an active ingredient. Examples include a singleadministration of a slow release composition, a course of treatmentinvolving several treatments on a regular or irregular basis, multipleadministrations for a period of time until a diminution of the diseasestate is achieved, preventative treatments applied prior to theinstigation of symptoms, or any other dosing regimen known in the art oryet to be disclosed that one skilled in the art would recognize as apotentially effective regimen. A final dosing regimen including theregularity of and mode of administration will be dependent on any of anumber of factors including but not limited to the subject beingtreated; the severity of the affliction; the manner of administration,the stage of disease development, the presence of one or more otherconditions such as pregnancy, infancy, or the presence of one or moreadditional diseases that affects the choice of the mode ofadministration, the dose to be administered and the time period overwhich the dose is administered.

Pharmaceutical compositions that include the compounds of formula HI orV may be administered prior to, concurrently with, or afteradministration of a second pharmaceutical composition that may or maynot include the compound. If the compositions are administeredconcurrently, they are administered within one minute of each other. Ifnot administered concurrently, the second pharmaceutical composition maybe administered a period of one or more minutes, hours, days, weeks, ormonths before or after the pharmaceutical composition that includes thecompound.

Alternatively, a combination of pharmaceutical compositions may becyclically administered. Cycling therapy involves the administration ofone or more pharmaceutical compositions for a period of time, followedby the administration of one or more different pharmaceuticalcompositions for a period of time and repeating this sequentialadministration, in order to reduce the development of resistance to oneor more of the compositions, to avoid or reduce the side effects of oneor more of the compositions, and/or to improve the efficacy of thetreatment.

The invention further encompasses kits that facilitate theadministration of the disclosed compound to a diseased entity. Anexample of such a kit includes one or more unit dosages of the compoundsof formula III or V. The unit dosage would be enclosed in a preferablysterile container and would be comprised of the compound(s) of formulaIII and V and a pharmaceutically acceptable carrier. In another aspect,the unit dosage would comprise one or more lyophilates of the compound.In this aspect of the invention, the kit may include another preferablysterile container enclosing a solution capable of dissolving thelyophilate. However, such a solution need not be included in the kit andmay be obtained separately from the lyophilate. In another aspect, thekit may include one or more devices used in administrating the unitdosages or a pharmaceutical composition to be used in combination withthe compound. Examples of such devices include, but are not limited to,a syringe, a drip bag, a patch or an enema. In some aspects of theinvention, the device comprises the container that encloses the unitdosage.

Pharmaceutical compositions of the compounds of formula III or V areused in methods of treating cancer. Such methods involve theadministration of a therapeutic amount of a pharmaceutical compositionof the compound of formula III or V and/or a pharmaceutically acceptablesalt thereof to a mammal in which a cancer has been diagnosed.

A therapeutic amount further includes the prevention of progression ofthe cancer to a neoplastic, malignant or metastatic state. Suchpreventative use is indicated in conditions known or suspected ofpreceding progression to neoplasia or cancer, in particular, wherenon-neoplastic cell growth consisting of hyperplasia, metaplasia, ormost particularly, dysplasia has occurred (for review of such abnormalgrowth conditions, see Robbins and Angell, 1976, Basic Pathology, 2dEd., W.B. Saunders Co., Philadelphia, pp. 68-79). Hyperplasia is a formof controlled cell proliferation involving an increase in cell number ina tissue or organ, without significant alteration in structure oractivity. For example, endometrial hyperplasia often precedesendometrial cancer and precancerous colon polyps often transform intocancerous lesions. Metaplasia is a form of controlled cell growth inwhich one type of adult or fully differentiated cell substitutes foranother type of adult cell. Metaplasia can occur in epithelial orconnective tissue cells. A typical metaplasia involves a somewhatdisorderly metaplastic epithelium. Dysplasia is frequently a forerunnerof cancer, and is found mainly in the epithelia; it is the mostdisorderly form of non-neoplastic cell growth, involving a loss inindividual cell uniformity and in the architectural orientation ofcells. Dysplastic cells often have abnormally large, deeply stainednuclei, and exhibit pleomorphism. Dysplasia characteristically occurswhere there exists chronic irritation or inflammation, and is oftenfound in the cervix, respiratory passages, oral cavity, and gallbladder.

Alternatively or in addition to the presence of abnormal cell growthcharacterized as hyperplasia, metaplasia, or dysplasia, the presence ofone or more characteristics of a transformed phenotype or of a malignantphenotype, displayed in vivo or displayed in vitro by a cell samplederived from a patient can indicate the desirability ofprophylactic/therapeutic administration of the pharmaceuticalcomposition that includes the compound. Such characteristics of atransformed phenotype include morphology changes, looser substratumattachment, loss of contact inhibition, loss of anchorage dependence,protease release, increased sugar transport, decreased serumrequirement, expression of fetal antigens, disappearance of the 250,000dalton cell surface protein, etc. (see also id., at pp. 84-90 forcharacteristics associated with a transformed or malignant phenotype).Further examples include leukoplakia, in which a benign-appearinghyperplastic or dysplastic lesion of the epithelium, or Bowen's disease,a carcinoma in situ, are pre-neoplastic lesions indicative of thedesirability of prophylactic intervention. In another example,fibrocystic disease including cystic hyperplasia, mammary dysplasia,adenosis, or benign epithelial hyperplasia is indicates desirability ofprophylactic intervention.

In some aspects of the invention, use of the disclosed compounds may bedetermined by one or more physical factors such as tumor size and gradeor one or more molecular markers and/or expression signatures thatindicate prognosis and the likely response to treatment with thecompound. For example, determination of estrogen (ER) and progesterone(PR) steroid hormone receptor status has become a routine procedure inassessment of breast cancer patients. See, for example, Fitzgibbons etal, Arch. Pathol. Lab. Med. 124:966-78, 2000. Tumors that are hormonereceptor positive are more likely to respond to hormone therapy and alsotypically grow less aggressively, thereby resulting in a betterprognosis for patients with ER+/PR+ tumors. In a further example,overexpression of human epidermal growth factor receptor 2 (HER-2/neu),a transmembrane tyrosine kinase receptor protein, has been correlatedwith poor breast cancer prognosis (see, e.g., Ross et al, The Oncologist8:307-25, 2003), and Her-2 expression levels in breast tumors are usedto predict response to the anti-Her-2 monoclonal antibody therapeutictrastuzumab (Herceptine, Genentech, South San Francisco, Calif.).

In another aspect of the invention, the diseased entity exhibits one ormore predisposing factors for malignancy that may be treated byadministration of a pharmaceutical composition including the compound.Such predisposing factors include but are not limited to chromosomaltranslocations associated with a malignancy such as the Philadelphiachromosome for chronic myelogenous leukemia and t (14; 18) forfollicular lymphoma; an incidence of polyposis or Gardner's syndromethat are indicative of colon cancer; benign monoclonal gammopathy whichis indicative of multiple myeloma, kinship with persons who have had orcurrently have a cancer or precancerous disease, exposure tocarcinogens, or any other predisposing factor that indicates inincreased incidence of cancer now known or yet to be disclosed.

The invention further encompasses methods of treating cancer thatcomprise combination therapies that comprise the administration of apharmaceutical composition including the disclosed compound and anothertreatment modality. Such treatment modalities include but are notlimited to, radiotherapy, chemotherapy, surgery, immunotherapy, cancervaccines, radioimmunotherapy, treatment with pharmaceutical compositionsother than those which include the compounds of formula III or V, or anyother method that effectively treats cancer in combination with thecompounds of formula III or V. Combination therapies may actsynergistically. That is, the combination of the two therapies is moreeffective than either therapy administered alone. This results in asituation in which lower dosages of both treatment modality may be usedeffectively. This in turn reduces the toxicity and side effects, if any,associated with the administration either modality without a reductionin efficacy.

In another aspect of the invention, the pharmaceutical compositionincluding the compounds of formula III or V is administered incombination with a therapeutically effective amount of radiotherapy. Theradiotherapy may be administered concurrently with, prior to, orfollowing the administration of the pharmaceutical composition includingthe compound. The radiotherapy may act additively or synergisticallywith the pharmaceutical composition including the compound. Thisparticular aspect of the invention would be most effective in cancersknown to be responsive to radiotherapy. Cancers known to be responsiveto radiotherapy include, but are not limited to, Non-Hodgkin's lymphoma,Hodgkin's disease, Ewing's sarcoma, testicular cancer, prostate cancer,ovarian cancer, bladder cancer, larynx cancer, cervical cancer,nasopharynx cancer, breast cancer, colon cancer, pancreatic cancer, headand neck cancer, esophageal cancer, rectal cancer, small-cell lungcancer, non-small cell lung cancer, brain tumors, other CNS neoplasms,or any other such tumor.

Additional cancers that can be treated by pharmaceutical compositions ofthe compounds of formula III or V include blood borne cancers such asacute lymphoblastic leukemia (“ALL,”), acute lymphoblastic B-cellleukemia, acute lymphoblastic T-cell leukemia, acute myeloblasticleukemia (“AML”), acute promyelocytic leukemia (“APL”), acutemonoblastic leukemia, acute erythroleukemic leukemia, acutemegakaryoblastic leukemia, acute myelomonocytic leukemia, acutenonlymphocyctic leukemia, acute undifferentiated leukemia, chronicmyelocytic leukemia (“CML”), chronic lymphocytic leukemia (“CLL”), hairycell leukemia, multiple myeloma, lymphoblastic leukemia, myelogenousleukemia, lymphocytic leukemia, myelocytic leukemia, Hodgkin's disease,non-Hodgkin's Lymphoma, Waldenstrom's macroglobulinemia, Heavy chaindisease, and Polycythemia vera.

The compounds of formula III or V can be used to treat cancer and totreat neurodegenerative disorders, auto-immune disorders, cardiovasculardisorders, metabolic disorders, hamartoma syndrome, genetic muscledisorders, and myopathy. It is to be understood that each of thecompounds of formulas III and V as recited herein are useful for anumber of the above conditions, but not each and every compound isuseful for each and every condition. It is well within the ability ofthose skilled in the art to easily determine which particular compoundof formula III or V is useful for each particular condition withoutundue experimentation.

Further, compounds of formulas III and V can be used as cytostaticadjuvants to most small molecule/chemotherapy regimens, but thecompounds also can be used as single agents. The compounds of formulasHI and V can thus be used in combination with other drugs.

Determination of an effective amount of the disclosed compounds iswithin the capability of those skilled in the art, especially in lightof the detailed disclosure provided herein. The effective amount of apharmaceutical composition used to effect a particular purpose, as wellas its toxicity, excretion, and overall tolerance is determined in cellcultures, or animals by pharmaceutical and toxicological proceduresknown to those skilled in the art. For example, in clinical practice thecompounds of formula III and V will normally be administered 1-4 timesdaily; orally, rectally, parenterally, or other route of administrationin an appropriate pharmaceutical compositions containing the activeingredient either as a free base or as a pharmaceutically acceptableacid addition salt in association with one or more pharmaceuticallyacceptable carriers. Suitable daily doses of the compounds of formula HIand V are from about 0.1 to about 100 mg/kg for oral administration,preferably from about 0.5 to about 50 mg/kg, and from about 0.01 toabout 50 mg/kg for parenteral administration, preferably from about 0.03to about 3 mg/kg. The use and administration to a patient to be treatedin the clinic would be readily apparent to a person of ordinary skill inthe art.

The exact dosage and frequency of administration depends on theparticular compound of formula III or V used, the particular conditionbeing treated, the severity of the condition being treated, the age,weight, general physical condition of the particular patient, othermedication the individual may be taking as is well known to thoseskilled in the art and can be more accurately determined by measuringthe blood level or concentration of the compound of formula HI or V inthe patient's blood and/or the patients response to the particularcondition being treated.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

Example 1: 6-Chloro-N-(1-ethylpiperidin-4-yl)-2-methoxyacridin-9-amine

A mixture of 6,9-dichloro-2-methoxyacridine (100 mg, 0.36 mmol) andphenol (approximately 1.5 g) was heated to 100° C. under nitrogenatmosphere and stirred for 1 hour. 1-Ethylpiperidin-4-amine (92 mg, 0.72mmol) was added to the mixture. The reaction was stirred at 100° C. for5 hours, cooled to 20-25° C., and diluted with dichloromethane. Themixture was washed twice with sodium hydroxide solution (1 N) and twicewith ammonium chloride solution. The phases were separated, and theorganic layer was dried and concentrated. The residue was purified byBiotage column chromatography using triethylamine (5%) and methanol (5to15%) in dichloromethane to give the title compound; MS (Found:M+1=370).

Example 2:6-Chloro-N-(2-(2-(diethylamino)ethoxy)ethyl)-2-methoxyacridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations, but using 6,9-dichloro-2-methoxyacridine and commerciallyavailable 2-(2-aminoethoxy)-N,N-diethylethanamine, the title compoundwas obtained; MS (Found M+1=402).

Example 3: 6-Chloro-2-methoxy-N-(4-methoxybutyl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations, but using 6,9-dichloro-2-methoxyacridine and commerciallyavailable 4-methoxybutan-1-amine, the title compound was obtained; MS(Found M+1=345).

Example 4:6-Chloro-2-methoxy-N-(4-(pyrrolidin-1-yl)butyl)acridin-9-amine

Step 1. Synthesis of 4-(benzyloxycarbonylamino)butyl methanesulfonate

To a solution of benzyl 4-hydroxybutylcarbamate (1.1 g, 4.9 mmol) andtriethylamine (1.7 mL, 9.8 mmol) in THF was added methanesulfonylchloride (0.67 g, 5.9 mmol) at 0° C. The reaction was stirred at 20-25°C. for 6 hours and concentrated. The residue was partitioned betweenethyl acetate and water. The phases were separated, and the organiclayer was washed with hydrochloride solution (1 N), saturated sodiumbicarbonate solution, and saline. The separated organic layer was driedand concentrated to give 4-(benzyloxycarbonylamino)butylmethanesulfonate (1.2 g).

Step 2. Synthesis of benzyl 4-(pyrrolidin-1-yl)butylcarbamate

To a pressure vessel was added 4-(benzyloxycarbonylamino)butylmethanesulfonate (330 mg, 1.10 mmol) and pyrrolidine (234 mg, 3.3 mmol)in THF. The reaction was heated to 100° C., stirred overnight, cooled to20-25° C., and concentrated. The crude concentrate was purified byBiotage column chromatography to give benzyl4-(pyrrolidin-1-yl)butylcarbamate (200 mg).

Step 3. Synthesis of 4-(pyrrolidin-1-yl)butan-1-amine

To a solution of benzyl 4-(pyrrolidin-1-yl)butylcarbamate (196 mg, 0.71mmol) was added catalytic amount of Pd/C (5%). The reaction was stirredunder a hydrogen atmosphere overnight and filtered. The filtrate wasconcentrated to give 4-(pyrrolidin-1-yl)butan-1-amine (83 mg)

Step 4. Synthesis of the Title Compound

Following the general procedure of Example 1 and making non-criticalvariations, but using 6,9-dichloro-2-methoxyacridine and4-(pyrrolidin-1-yl)butan-1-amine (Step 3), the title compound wasobtained; MS (Found M+1=384).

Example 5:N¹-tert-butyl-N⁴-(6-chloro-2-methoxyacridin-9-yl)butane-1,4-diamine

Following the general procedure of Example 1 and making non-criticalvariations, but using 6,9-dichloro-2-methoxyacridine and commerciallyavailable N¹-tert-butylbutane-1,4-diamine, the title compound wasobtained; MS (Found M+1=386).

Example 6:N-(4-(6-Chloro-2-methoxyacridin-9-ylamino)butyl)-N-ethylmethanesulfonamide

Step 1. Synthesis of benzyl 4-(ethylamino)butylcarbamate

Following the general procedure of Example 4, Step 2, and makingnon-critical variations but using 4-(benzyloxycarbonylamino)butylmethanesulfonate and ethyl amine in THF, the compound of Step 1 wasobtained.

Step 2. Synthesis of benzyl 4-(N-ethylmethylsulfonamido)butylcarbamate

To a mixture of benzyl 4-(ethylamino)butylcarbamate (Step 1, 250 mg,1.00 mmol) in dichloromethane was added pyridine (145 mg, 1.8 mmol) andthen methanesulfonyl chloride (137 mg, 1.20 mmol) at 0° C. The reactionwas stirred overnight and diluted with dichloromethane. The phases wereseparated, and the organic phase was washed with hydrochloride solution(1 N), saturated sodium bicarbonate and saline. The separated organiclayer was concentrated and purified by Biotage column chromatography togive benzyl 4-(N-ethylmethylsulfonamido)butylcarbamate (231 mg).

Step 3. Synthesis of N-(4-aminobutyl)-N-ethylmethanesulfonamide

Following the general procedure of Example 4, Step 3, but using benzyl4-(N-ethyhlmethylsulfonamido)butylcarbamate (Step 2), the compound ofStep 3 was obtained.

Step 4. Synthesis of the title compound

Following the general procedure of Example 1 and making non-criticalvariations, but using 6,9-dichloro-2-methoxyacridine andN-(4-aminobutyl)-N-ethylmethanesulfonamide (Step 3), the title compoundwas obtained; MS (Found M+1=436).

Example 7:6-Chloro-2-methoxy-N-(4-(4-methylpiperazin-1-yl)butyl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations, but using 6,9-dichloro-2-methoxyacridine and commerciallyavailable 4-(4-methylpiperazin-1-yl)butan-1-amine, the title compoundwas obtained, MS (Found M+1=413. ¹H NMR (CD₃OD, 300 Hz): 8.32-8.30 (d,1H J=8.2 Hz), 8.30-7.85 (m, 1H), 7.58-7.57 (d, 1H), 7.47-7.44 (m, 1H),7.34-7.32 (m, 1H), 4.00 (s, 3H), 3.92-3.89 (t, 2H, J=6 Hz), 2.54-2.51(b, 4H), 2.41-2.29 (m, 6H), 2.25 (s, 3H), 1.85-1.77 (m, 2H), 1.60-1.53(m, 2H).

Example 8: 3-Chloro-N-(1-ethylpiperidin-4-yl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations, but using 3,9-dichloroacridine (J. Med. Chem. 1985, 28.940-944) and 1-ethylpiperidin-4-amine, the title compound was obtained;MS (Found M+1=340).

Example 9:N-(4-(6-Chloro-2-methoxyacridin-9-ylamino)butyl)-N-ethylacetamide

Step 1. Synthesis of N-(4-aminobutyl)-N-ethylacetamide

Following the general procedure of Example 6, Steps 2 and 3, and makingnon-critical variations N-(4-aminobutyl)-N-ethylacetamide was obtained.

Step 2. Synthesis of the Title Compound

Following the general procedure of Example 1, and making non-criticalvariations but using 6,9-dichloro-2-methoxyacridine andN-(4-aminobutyl)-N-ethylacetamide (Step 1), the title compound wasobtained; MS (Found M+1=400).

Example 10:N¹-(6-Chloro-2-methoxyacridin-9-yl)-N⁴-(cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine

Step 1. Synthesis of N¹-(cyclopropylmethyl)-N¹-methylbutane-1,4-diamine

Following the general procedure of Example 4, Steps 2 and 3, and makingnon-critical variations but using 4-(benzyloxycarbonylamino)butylmethanesulfonate and commercially available1-cyclopropyl-N-methylmethanamine,N¹-(cyclopropylmethyl)-N¹-methylbutane-1,4-diamine was obtained.

Step 2. Synthesis of Title Compound

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-2-methoxyacridine andN¹-(cyclopropylmethyl)-N¹-methylbutane-1,4-diamine (Step 1), the titlecompound was obtained; MS (Found M+1=398). ¹H NMR (CDCl₃, 300 Hz):8.05-7.94 (m, 3H), 7.40-7.36 (m, 1H), 7.26-7.23 (m, 2H), 3.93 (s, 3H),3.75-3.71 (t, 2H, J=6 Hz), 2.48-2.43 (t, 2H, J=6 Hz), 2.29-2.22 (m, 5H),1.85-1.78 (m, 2H), 1.76-1.65 (m, 2H), 0.87-0.85 (m, 1H), 0.50-0.45 (d,2H, J=2.4 Hz), 0.09-0.05 (d, 2H, J=4.8 Hz).

Example 11: 6-Chloro-2-methoxy-N-(2-methoxyethyl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-2-methoxyacridine and2-methoxyethanamine, the title compound was obtained; MS (FoundM+1=317).

Example 12:N¹-(6-Chloro-2-methoxyacridin-9-yl)-N⁴-cyclopropyl-N⁴-ethylbutane-1,4-diamine

Step 1. Synthesis of benzyl 4-(cyclopropyl(ethyl)amino)butylcarbamate

Following the general procedure of Example 4, Step 2, and makingnon-critical variations but using 4-(benzyloxycarbonylamino)butylmethanesulfonate and commercially available N-ethylcyclopropanamine,benzyl 4-(cyclopropyl(ethyl)amino)butylcarbamate was obtained.

Step 2. N¹-cyclopropyl-N¹-ethylbutane-1,4-diamine HCl salt

The mixture of benzyl 4-(cyclopropyl(ethyl)amino)butylcarbamate (Step 1)in HCl (6 N) was heated to reflux for 1 hour and cooled to 20-25° C. Thereaction mixture was concentrated, and the residue was dried underreduced pressure to give N¹-cyclopropyl-N¹-ethylbutane-1,4-diamine HClsalt.

Step 3. Synthesis of the Title Compound

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-2-methoxyacridineN¹-cyclopropyl-N¹-ethylbutane-1,4-diamine HCl salt (Step 2) anddiisopropyethylamine (4 eq), the title compound was obtained; MS (FoundM+1=398).

Example 13:N¹46-Chloro-2-methoxyacridin-9-yl)-N⁴-(cyclopropylmethyl)-N⁴-ethylbutane-1,4-diamine

Step 1. Synthesis of N¹-(cyclopropylmethyl)-N¹-ethylbutane-1,4-diamine

Following the general procedure of Example 4, Step 2, and makingnon-critical variations but using 4-(benzyloxycarbonylamino)butylmethanesulfonate and N-(cyclopropylmethyl)ethanamine,N¹-(cyclopropylmethyl)-N¹-ethylbutane-1,4-diamine was obtained

Step 2. Synthesis of the Title Compound

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-2-methoxyacridine,N¹-(cyclopropylmethyl)-N¹-ethylbutane-1,4-diamine (Step 1), the titlecompound is obtained; MS (Found M+1=412).

Example 14:N¹-(6-Chloro-2-methoxyacridin-9-yl)-N⁴,N⁴-diethyl-N¹-methylbutane-1,4-diamine

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-2-methoxyacridine andN¹,N¹-diethyl-N⁴-methylbutane-1,4-diamine, the title compound wasobtained. MS (Found M÷1=400).

Example 15: N-(1-Ethylpiperidin-4-yl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 9-chloroacridine and 1-ethylpiperidin-4-amine, thetitle compound was obtained; MS (Found M+1=306).

Example 16: 6-Chloro-N-(1-ethylpiperidin-4-yl)-2-fluoroacridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-2-fluoroacridine (J. Med. Chem. 1985,28, 940-944) and 1-ethylpiperidin-4-amine, the title compound wasobtained; MS (Found M+1=358).

Example 17:6-Chloro-2-fluoro-N-(2-(4-methylpiperazin-1-yl)ethyl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-2-fluoroacridine and2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained;MS (Found M+1=373).

Example 18: N-(1-Ethylpiperidin-4-yl)-6-fluoro-2-methoxyacridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 9-dichloro-6-fluoro-2-methoxyacridine and1-ethylpiperidin-4-amine, the title compound was obtained; MS (FoundM+1=354).

Example 19: 3-Chloro-N-(2-(4-methylpiperazin-1-yl)ethyl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 3,9-dichloroacridine (J. Med. Chem. 1985, 28.940-944) and 2-(4-methylpiperazin-1-yl)ethanamine, the title compoundwas obtained; MS (Found M+1=355).

Example 20:6-Fluoro-2-methoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 9-dichloro-6-fluoro-2-methoxyacridine and2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained;MS (Found M4-1=369).

Example 21:6-Chloro-2-methoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-2-methoxyacridine and2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained;MS (Found M+1=385).

Example 22: 6-Chloro-2-methoxy-N-(1-methylpiperidin-4-yl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-2-methoxyacridine and1-methylpiperidin-4-amine, the title compound was obtained; MS (FoundM+1=356).

Example 23:7-Chloro-2-methoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzo[b][1,5]naphthyridin-10-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 7,10-dichloro-2-methoxypyrido[3,2-b]quinoline and2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained;MS (Found M+1=386). ¹H NMR (DMSO-d6, 400 Hz): 8.43-8.41 (d, 1H, J=9.2Hz), 8.12-8.10 (d, 1H, J=9.2 Hz), 7.87 (b, 1H), 7.2 (s, 1H), 7.2.9-7.27(d, 1H, J=9.2 Hz) 7.25-7.24 (d, 1H, J=9.2 Hz), 4.10 (m, 2H), 4.06 (s,3H), 2.70-2.68 (m, 2H), 2.33 (b, 8H), 2.14 (s, 3H).

Example 24:7-Chloro-N-(1-ethylpiperidin-4-yl)-2-methoxybenzo[b][1,5]naphthyridin-10-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 7,10-dichloro-2-methoxypyrido[3,2-b]quinoline and1-ethylpiperidin-4-amine, the title compound was obtained; MS (FoundM+1=371). ¹H NMR (DMSO-d6, 400 Hz): 8.43-8.42 (d, 1H, J=9.2 Hz),8.11-8.10 (d, 1H, J=9.2 Hz), 7.84 (s, 1H), 7.37-7.35 (d, 1H, J=9.2 Hz)7.25-7.23 (d, 1H, J=9.2 Hz), 6.95 (b, 1H), 4.98 (b, 1H), 4.00 (s, 3H),2.85 (b, 2H), 2.30 (b, 2H), 2.02-1.99 (m 4H), 1.00-1.97 (t, 3H, J=7.2Hz).

Example 25: N-(1-Ethylpiperidin-4-yl)-2-methoxyacridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 9-chloro-2-methoxyacridine and1-ethylpiperidin-4-amine, the title compound was obtained; MS (FoundM+1=336). ¹H NMR (CD₃OD, 400 Hz): 8.2.9-8.27 (d, 1H, J=8.8 Hz),7.96-7.94 (d, 1H, J=8.8 Hz), 7.92-7.89 (d, 1H, J=9.6 Hz), 7.70-7.66 (m,1H), 7.53 (m, 1H), 7.46-7.43 (m, 2H), 3.98 (s, 3H), 3.90-3.80 (m, 1H),3.02-3.8 (bm, 2H), 2.46-2.41 (q, 2H, J=7.2 Hz), 2.05-2.00 (m, 4H),1.93-1.83 (m, 2H), 1.11-1.08 (t, 3H, J=7.2 Hz).

Example 26:6-Chloro-N-(1-ethylpiperidin-4-yl)-1,2,3,4-tetrahydroacridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-1,2,3,4-tetrahydroacridine and1-ethylpiperidin-4-amine, the title compound was obtained; MS (FoundM+1=344).

Example 27:6-Chloro-N-(2-(4-methylpiperazin-1-yl)ethyl)-1,2,3,4-tetrahydroacridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-1,2,3,4-tetrahydroacridine and2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained;MS (Found M+1=359). ¹H NMR (CDCl3, 300 Hz): 7.97-7.95 (m, 2H, J=9 Hz),7.95-7.91 (d, 1H, J=9 Hz), 7.28-7.25 (m, 1H), 5.25 (h, 1H), 3.58-3.49(m, 2H), 3.05 (m, 2H), 3.73 (m, 2H), 2.63-2.59 (m 10H), 2.39 (s, 3H),1.94-1.90 (m, 4H).

Example 28:6-Chloro-2-methoxy-N-(1-methylpyrrolidin-3-yl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations but using 6,9-dichloro-2-methoxyacridine and1-methylpyrrolidin-3-amine, the title compound was obtained; MS (FoundM+1=356)

Example 29:6-Chloro-2-fluoro-N-(1-(4-methylpiperazin-1-yl)propan-2-yl)acridin-9-amine

Following the general procedure of Example 1 and making non-criticalvariations and starting with the appropriate starting materials, thetitle compound was obtained.

Examples 30-56 in Table 1 were prepared according to the above examplesusing appropriate starting materials. MS data is summarized for thecompounds in Table 2.

TABLE 2 Example MS m/z (M + 1) 30 334.2 31 352.1 32 368.2 33 364.2 34443.3 35 382.1 36 386.1 37 403.1 38 368.2 39 385.1 40 369.2 41 403.2 42399.2 43 372.1 44 358.1 45 384.2 46 370.2 47 412.2 48 426.2 49 442.1 50442.1 51 428.2 52 426.2 53 462.1 54 384.2 55 385.1 56 384.1 64 400.0

Biological Example 1

Tumor cell lines (H292, HCT116, A375, HCC1569, A498, N87, UACC1093, andUACC647) were cultured in RPMI 1640 supplemented with 5% fetal bovineserum and housed in a 5% CO₂ Incubator at 37° C.

For single agent IC₅₀ determination, cells were plated on a 96 wellmicroplate and allowed 24 hours to adhere. Drugs were administered tothe drug plate by the following: compound stock solutions (10 mM) wereadded to a drug plate where a 1:10 dilution was performed. Following thedilutions, 2 μl of test compound was transferred to the correspondingwells in the cell-containing 96-well plate with 198 μl of growth media.The compounds were tested over a range of 0.1 pM-100 μM for 72 hours.Following 72 hours of continuous exposure cell viability was determinedby measuring the ATP activity using a commercially available cellviability assay kit. Luminescence intensity was used to relative drugactivity compared to control wells and used to graphically determine theIC₅₀.

For combination interaction experiments, cells were plated on a 96 wellmicroplate and allowed 24 hours to adhere. Drugs were administered tothe drug plate by the following: compound stock solutions (20 mM) orcombination agent stock solutions (20 mM) were added to a drug platewhere a 1:10 dilution was performed. Following the dilutions, 2 μl ofeach VT-062 and standard agent was transferred to the correspondingwells in the cell-containing 96-well plate with 196 μl of growth media.The compound and combination agent was concurrently tested over a rangeof 0.1 pM-100 μM for 72 hours. Following 72 hours of continuous exposurecell viability was determined by measuring the ATP activity using acommercially available cell viability assay kit. Luminescence intensitywas used to relative drug activity compared to control wells and used tographically determine the IC₅₀ of combination.

FIGS. 1A, 1B, and C show that Example 10 inhibited tumor cell growth bymore than 75% in the cell lines tested. FIGS. 3A, 3B, and 3C showsimilar tumor growth inhibition for Examples 7, 26, and 27 in A375 tumorcells.

FIGS. 4A and 4C show that Example 10 in combination with PLX-4032 had a2.6-3.25% increase in tumor growth inhibition against in combinationthan Example 10 alone in PLX-4032 resistant melanoma cell lines. FIGS.4B and 4D show that Example 10 in combination with Temozelomide had a7-30% increase in tumor growth inhibition in combination than Example 10alone in those same cell lines.

Biological Example 2: Autophagy Inhibition Screen and Quantification

U2OS cells stably expressing ptfLC3 (Adgene plasmid 21074) (Kimura, etal., 2007) were seeded at 5,000 cells per well in 5A McCoy's medium(Invitrogen, Carlsbad, Calif.) with 10% fetal bovine serum (FBS,Invitrogen) in 96-well glass bottom tissue culture plates for 24 hoursat 37° C. and 5% CO₂. Cells were treated with VATG compounds in a10-point dose response for three hours, fixed with 3.7% formaldehyde,and nuclei were stained with Hoechst 33342 (Invitrogen). Cells werevisualized using a 60× oil-immersion objective on a Nikon fluorescentmicroscope and pftLC3 fluorescence was compared with that of a DMSOvehicle control within each plate. Doses were qualitatively scored basedon increased accumulation of ptfLC3 labeled punctae from zero punctaeand higher.

An ED was then established for each compound. The compounds wererepeated alongside chloroquine and quinacrine on U2OS cells seeded at50,000 cells per well in 5A McCoy's with 10% FBS on number 1.5coverglasses in 24-well tissue culture dishes. After 24 hours, the cellswere treated at set doses of 0.3 uM, 1 uM, 3 uM, 10 uM, and 30 uM forthree hours for confirmation. Cells were washed with 1×PBS, fixed with3.7% formaldehyde, and nuclei were stained with Hoechst 33342 (2 ug/mL).Coverglasses were inverted onto a microscope slide using mounting gel.The microscope slides were imaged using a 60× oil-immersion objective ona Nikon Eclipse Ti fluorescent microscope and 10 images at each dosewere taken for quantification. Image processing and quantification werecompleted with the Nikon NIS Elements software. To quantify, images weredeconvoluded using a 2E) blind deconvolution function with one iterationand settings of normal cell thickness and normal noise level. Regions ofinterest (ROI) were drawn around the edges of each cell excluding thenuclear region. Intensity thresholds were set to include all pixelsequal to or greater than the intensity above the mean backgroundfluorescence. Objects within the threshold ROIs were quantified using anautomated object count function and exported to Excel (Microsoft).Although other parameters were also collected, the mean intensity of theobjects was averaged between the 10 images of each dose, orapproximately 35 cells. Representative images were chosen for each doseand the LUTs were set based on the mean intensity of the DMSO control.The mean intensity of each image was divided by the mean intensity ofthe DMSO control and the LUTs were adjusted by the percent difference toavoid viewing the background intensity.

The quantified ED₅₀ values are shown in Table 3.

TABLE 3 Example Autophagy Inhibition (ED50) 1 ***** 2 ***** 3 * 4 *****5 ***** 6 * 7 ***** 8 *** 9 * 10 ***** 11 * 12 *** 13 ***** 14 * 15***** 16 *** 17 *** 18 *** 19 *** 20 *** 21 ***** 22 *** 23 ***** 24 ***25 ***** 26 ***** 27 *** 28 ***

Biological Example 3: Human Tumor Xenograft Study

Female mice were inoculated subcutaneously in the right flank with 0.1ml of a 50% RPMI/50% Matrigel™ (BD Biosciences, Bedford, Mass.) mixturecontaining a suspension of A375 Human melanoma tumor cells(approximately 5×10⁶ cells/mouse).

When tumor reached approximately 130 mg, mice were randomized intotreatment groups. Body weights were recorded when the mice wererandomized and were taken twice per week (on Study Days 3 and 7 for eachcycle) thereafter in conjunction with tumor measurements. Treatmentbegan on the day of randomization. Example 10 was delivered orally in avehicle consisting of 5% DMA, 10% propylene glycol, 20% PEG 400, and 65%sterile water. Example 10 was administered daily for 21 days.

FIG. 5 shows that tumor weight in mice over the course of 25 days.Example 10 inhibited tumor growth by greater than 50% after 25 days.

Biological Example 4: Autophagy Inhibition Screen and Quantification

U2OS cells stably expressing ptfLC3 (Adgene plasmid 21074) (Kimura, etal., 2007) were seeded at 5,000 cells per well in 5A McCoy's medium(Invitrogen, Carlsbad, Calif.) with 10% fetal bovine serum (FBS,Invitrogen) in 96-well glass bottom tissue culture plates for 24 hoursat 37° C. and 5% CO₂. Cells were treated with compounds in a 10-pointdose response for three hours, fixed with 3.7% formaldehyde, and nucleiwere stained with. Hoechst 33342 (Invitrogen). Cells were visualizedusing a 60× oil-immersion objective on a Nikon fluorescent microscopeand pftLC3 fluorescence was compared with that of a DMSO vehicle controlwithin each plate. Doses were qualitatively scored based on increasedaccumulation of ptfLC3 labeled punctae from zero punctae and higher. AnED was established for each compound. The compounds selected, Example 7and Example 26, were repeated on U2OS cells seeded at 50,000 cells perwell in 5A McCoy's with 10% FBS on number 1.5 coverglasses in 24-welltissue culture dishes. After 24 hours cells were treated at set doses of0.3 uM, 1 uM, 3 uM, 10 uM, and 30 uM for three hours for confirmation.Cells were washed with 1×PBS, fixed with 3.7% formaldehyde, and nucleiwere stained with Hoechst 33342 (24 mL). Coverglasses were inverted ontoa microscope slide using mounting gel. The microscope slides were imagedusing a 60× oil-immersion objective on a Nikon Eclipse Ti fluorescentmicroscope and 10 images at each dose were taken for quantification.Image processing and quantification were completed with the Nikon MSElements software. To quantify, images were deconvoluded using a 2Dblind deconvolution function with one iteration and settings of normalcell thickness and normal noise level. Regions of interest (ROI) weredrawn around the edges of each cell excluding the nuclear region.Intensity thresholds were set to include all pixels equal to or greaterthan the intensity above the mean background fluorescence. Objectswithin the threshold ROIs were quantified using an automated objectcount function and exported to Excel (Microsoft). Although otherparameters were also collected, the mean intensity of the objects wasaveraged between the 10 images of each dose, or approximately 35 cells.Representative images were chosen for each dose and the LUTs were setbased on the mean intensity of the DMSO control. The mean intensity ofeach image was divided by the mean intensity of the DMSO control and theLUTs were adjusted by the percent difference to avoid viewing thebackground intensity. FIG. 6A shows the mean intensities for Example 7and Example 26.

Biological Example 5: Cell Viability (LD₅₀) Screen

U2OS cells were seeded at 500 cells per well in 5A McCoy's with 10% FBSin 96-well clear bottom, black-walled tissue culture plates. After 24hour incubation, cells were treated with compounds in triplicate with a10-point half log dose response for 24 and 48 hours. Medium was removedwith 2× CellTiter Cilo (Promega) reagent mixed 1:1 with optimem(Invitrogen) was added at 100 uL per well and incubated rocking at roomtemperature for 15 minutes. A total of 75 uL per well was moved to awhite-walled 96-well plate and read using the 96 LUM program on anEnVision plate reader ( ) and exported to Excel (Microsoft) foranalysis. FIG. 6B shows the relative cell viabilities of Example 7 andExample 26.

Biological Example 6: Demonstrating an Inhibitory Lysosomal Mechanism ofAction

To determine deacidification of the lysosome, cells were incubated withLysoTracker Red, a dye that localizes to the lysosome based on the lowacidity of the compartment. If the lysosome is no longer acidic, thereis a loss in the amount of LysoTracker Red staining. Lysosomalinhibition was further determined by immunofluorescence oflysosome-associated membrane protein-1 (LAMP1). If the lysosome isinhibited, lysosomal turnover should decrease and an increase in theamount of LAMP1 staining would be apparent. U2OS cells were treated withExample 7 or Example 26 at 304 for 3 hours, supplementing LysoTrackerRed for the final hour. Example 7 and Example 26 treatments all causedsubstantial increases in LAMP1 staining and essentially ablatedLysoTracker Red staining, indicating that the compounds inhibitlysosomal turnover through deacidification.

Using image analysis software, the mean intensities of both the LAMP1and LysoTracker Red staining were measured and represent alteredintensity level between treatments on intensity plots. Individual pointswere measured using a line scan on the image analysis software, whichmeasures the intensity across the path of a line at any given point. Notonly does the presence of LAMP1 positive membranes increases, but theintensity in LAMP1 staining also increases with Example 7 and Example 26treatment. The inverse relationship in intensity holds true forLysoTracker Red staining. Treatment with Example 7 and Example 26 showedless intense LysoTracker Red staining, indicating an increase in pH.

Other Embodiments

The foregoing disclosure has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications can be made while remainingwithin the spirit and scope of the invention. It will be obvious to oneof skill in the art that changes and modifications can be practicedwithin the scope of the appended claims. Therefore, it is to beunderstood that the above description is intended to be illustrative andnot restrictive.

The scope of the invention should, therefore, be determined not withreference to the above description, but should instead be determinedwith reference to the following appended claims, along with the fullscope of equivalents to which such claims are entitled.

The invention claimed is:
 1. A compound of formula III

or a pharmaceutically acceptable salt thereof, wherein: Q is —CH; R_(N)is —H; R₁ is —H, —F, —Cl, —Br, or —CF₃; R₂ is —CH(R₂₋₁)-(CH₂)_(n2)—X;R₂₋₁ is —H, or —C₃ cycloalkyl; n₂ is 3; X is —NX₁₋₂X₁₋₃, wherein X₁₋₂ is—H, linear or branched —C₁-C₄ alkyl, -cyclopropyl, -cyclobutyl, or—SO₂—X₁₋₄, wherein X₁₋₄ is selected from the group consisting of: —H,—C₁-C₃ alkyl, and —CO—X₁₋₄, wherein X₁₋₄ is as defined above; X₁₋₃ islinear or branched —C₁-C₄ alkyl substituted with one cyclopropyl; R₃ is—H, —CF₃, —OR₃₋₁, wherein R₃₋₁ is —H, —C₁-C₆ alkyl, —CO—R₃₋₂, whereinR₃₋₂ is —C₁-C₃ alkyl or -phenyl, —N(R₃₋₁)₂, wherein the R₃₋₁ are thesame or different and are as defined above, —SR₃₋₁, wherein R₃₋₁ is asdefined above, —S(O)—R₃₋₁ wherein R₃₋₁ is as defined above, or—SO₂—R₃₋₁, wherein R₃₋₁ is as defined above; R₄ is —H, —F, —Cl, —Br,—CF₃, —OR₄₋₁, wherein R₄₋₁ is —H, C₁-C₆ alkyl or —CO—R₄₋₂, wherein R₄₋₂is C₁-C₃ alkyl or phenyl, —N(R₄₋₁)₂, wherein the R₄₋₁ are the same ordifferent and are as defined above, —SR₄₋₁, wherein R₄₋₁ is as definedabove, —S(O)—R₄₋₁, wherein R₄₋₁ is as defined above, or —SO₂—R₄₋₁,wherein R₄₋₁ is as defined above; and R₅ is —H, —F, —Cl, —Br, —CF₃,—OR₅₋₁, wherein R₅₋₁ is —H, —C₁-C₆ alkyl or —CO—R₅₋₂ wherein R₅₋₂ is—C₁-C₃ alkyl or -phenyl, —N(R₅₋₁)₂, wherein the R₅₋₁ are the same ordifferent and are as defined above, —SR₅₋₁, wherein R₅₋₁ is as definedabove, —S(O)—R₅₋₁, wherein R₅₋₁ is as defined above, or —SO₂—R₅₋₁,wherein R₅₋₁ is as defined above; with the proviso that one of R₁, R₃,R₄ and R₅ must be other than —H.
 2. The compound of claim 1, wherein: Xis

wherein X₁₋₂ is selected from the group consisting of: —H, linear orbranched —C₁-C₄ alkyl, -cyclopropyl, -cyclobutyl, and —SO₂—X₁₋₄, whereinX₁₋₄ is selected from the group consisting of: —H and —C₁-C₃ alkyl; andX₁₋₃ is a linear or branched —C₁-C₄ alkyl substituted with onecyclopropyl; R₃ is —H, —CF₃, —OR₃₋₁, wherein R₃₋₁ is —H or —C₁-C₆ alkyl,or —N(R₃₄)₂, wherein the R₃₋₁ are the same or different and are asdefined above, or —SR₃₋₁ wherein R₃₋₁ is as defined above; R₄ is —H, —F,—Cl, —Br, —CF₃, —OR₄₋₁ wherein R₄₋₁ is —H or —C₁-C₆ alkyl, —N(R₄₋₁)₂wherein the R₄₋₁ are the same or different and are as defined above, or—SR₄₋₁, wherein R₄₋₁ is as defined above; and R₅ is —H, —F, —Cl, —Br,—CF₃, —OR₅₋₁, wherein R₅₋₁ is —H or —C₁-C₆ alkyl, —N(R₅₄)₂, wherein theR₅₋₁ are the same or different and are as defined above, or —SR₅₋₁,wherein R₅₋₁ is as defined above; with the proviso that one of R₁, R₃,R₄, and R₅ must be other than —H.
 3. The compound of claim 2, wherein R₂is selected from the group consisting of:


4. The compound of claim 1, further comprising a pharmaceuticallyacceptable carrier, excipient, or diluent.
 5. A compound selected fromthe group consisting of: Example Structure Name 10

N¹-(6-Chloro-2- methoxyacridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine 12

N¹-(6-Chloro-2- methoxyacridin-9-yl)-N⁴- cyclopropyl-N⁴-ethylbutane-1,4-diamine 13

N¹-(6-Chloro-2- methoxyacridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴-ethylbutane-1,4-diamine 30

N¹-(acridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴- methylbutane-1,4-diamine31

N¹-(cyclopropylmethyl)-N⁴- (2-fluoroacridin-9-yl)-N¹-methylbutane-1,4-diamine 32

N¹-(2-chloroacridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine 33

N¹-(cyclopropylmethyl)-N⁴- (2-methoxyacridin-9-yl)-N¹-methylbutane-1,4-diamine 34

N¹-(6-bromo-2- methoxyacridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine 35

N¹-(cyclopropyl-methyl)-N⁴- (6-fluoro-2-methoxyacridin-9-yl)-N¹-methylbutane-1,4- diamine 36

N¹-(6-chloro-2-fluoroacridin- 9-yl)-N⁴-(cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine 37

N¹-(cyclopropylmethyl)-N⁴- (2,6-dichloroacridin-9-yl)-N¹-methylbutane-1,4-diamine 38

N¹-(3-chloroacridin-9-yl)-N⁴- (cyclopropylmethyl)-N⁴-methylbutane-1,4-diamine 41

N¹-(cyclopropylmethyl)-N⁴-(2,7- dichlorobenzo[b][1,5]naphthyridin-10-yl)-N¹-methylbutane-1,4- diamine 49

N⁴-(6-chloro-2-methoxyacridin-9- yl)-N¹-(cyclopropylmethyl)-5-methoxy-N¹-methylpentane-1,4- diamine 53

N-(4-(6-chloro-2-methoxyacridin- 9-ylamino)butyl)-N- (cyclopropylmethyl)methanesulfonamide 54

N¹-(6-chloro-2- methoxyacridin-9-yl)-N⁴- (cyclopropylmethyl)butane-1,4-diamine 56

N¹-(6-chloro-2-methoxyacridin-9- yl)-N⁴-cyclopropyl-N⁴-methylbutane-1,4-diamine.


6. The compound of claim 5, further comprising a pharmaceuticallyacceptable carrier, excipient, or diluent.
 7. The compound of claim 2,wherein R₂ consists of


8. The compound of claim 2, wherein R₂ consists of


9. The compound of claim 2, wherein R₂ consists of


10. The compound of claim 2, wherein R₂ consists of


11. The compound of claim 2, wherein R₂ consists of


12. The compound of claim 5, wherein the compound consists of


13. The compound of claim 5, wherein the compound consists of


14. The compound of claim 5, wherein the compound consists of